Int J App Pharm, Vol 17, Issue 1, 2025, 12-22Review Article

UNDERSTANDING NANO-BIO-INTERACTIONS WITH CORRESPONDING BIOLOGICAL RESPONSES: INSIGHTS AND IMPACT ON NANO ASSEMBLY AND DISASSEMBLY

POONAM JOSHI^1*, JYOTSANA SUYAL², TARUN PARASHAR³, SHIVANI RAWAT¹

¹Department of Pharmaceutical Sciences, School of Health Science and Technology, UPES, Dehradun, Uttarakhand, India. ²Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand, India. ³School of Pharmacyand Research, Dev Bhoomi Uttarakhand University, Dehradun-248007, Uttarakhand, India
^*Corresponding author: Poonam Joshi; ^*Email: poonamjoshi363602@gmail.com

Received: 26 Feb 2024, Revised and Accepted: 05 Nov 2024

ABSTRACT

Using stimuli-responsive Bio Interactions with controlled nano-assembly is proving a potent method for generating theranostic nanosystems that satisfy the needs of modern medicine for example, targeted delivery which is very helpful for cancer treatment with minimum side effects. However, because of the limitations in our knowledge, this promising topic is still in the proof-of-concept stage. This study provides an overview of the most recent theoretical and experimental advancements in biological fate, functional activity of nano-assemblies, and nano-bio interactions with exogenous stimulus-triggered systems (Light-responsive systems, Ultrasound-responsive systems, Magnetic field-responsive systems, and Thermal-responsive systems)endogenous stimulus-triggered systems (Ph-Responsive Systems, Redox-responsive systems, Enzyme-responsive systems) and multi stimuli system. Related biological consequences reactions. Firstly, we intend to thoroughly explain these relationships in this review. The relationship between interaction studies and nano-based stimuli; the important physicochemical characteristics of in vivo stimuli, such as responsive assembly and disassembly; biological applications; and pharmacokinetic (pk) parameters based on nano-bio interaction.

Keywords: Nano-bio interaction, Nanotechnology, 2-Dimensional, Assembly, Disassembly

© 2025 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2025v17i1.50745 Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

The Introduction and all sections of this review article were searched from specialized databases such as Elsevier, PubMed, Science Direct, Springer, and Google Scholar, and online published articles from the International Journal of Applied Pharmaceutics, Nature, JDDST, Nanomedicine, Nano Today, ACS Omega, etc. with searching keywords nano-bio interaction, Assembly, Disassembly, stimuli responsive. The range of the year of literature review article 1989-2023.

The range for nanoscale is 1 to 100 nanometres. Nanotechnology plays a vital role in pharmaceutical sciences, disease treatment, identification, etc. Nanotechnology gives facility to the targeted delivery, which is a very interesting topic for understanding how Nanomaterials (NMs) interact with biological molecules, to understand that concept, we discuss some important topics in this review. First, Nanomedicine entering into biological fluids, engineered nanomaterial can rapidly interact with various biomolecules, which mainly contain the three following aspects;

(1) Absorption of a biomolecule on the surface of nanomaterials (2) reconstruction and change of functional proteins and (3) redox reaction between nanomaterial and biomolecule.

Then, NMsenter the cell with different uptake inhibitors and state-of-the-art techniques such as transmission electron microscopy or confocal microscopy are used to study the cellular trafficking of NMs. The NMs react with the cells with uptake pathways, including the clathrin-mediated, caveolae-mediated, and lipid raft-mediated endocytosis and phagocytosis, as well as pinocytosis and micropinocytosis. Phagocytosis is normally for specialized cells such as monocytes and macrophages. Small size and protein adsorption in cell culture media, NMs are mostly consumed by cells through endocytosis, trapped into endosomes, entered into lysosomes, and then excluded from the cells. However, some NMs can get out of endosomes and enter other organelles such as cytosol, mitochondrion, and nucleus [1, 2].

How nano-based stimuli connect with interaction studies

Nano-based stimuli

The influence of nanotechnology in medicine is substantial, particularly in utilizing nanomaterials like metallic Nanoparticles (NPs), which offer numerous advantages. These intelligent nanomaterials are highly sought after due to their responsiveness to a range of extrinsic (e. g., optical, ultrasound, magnetic fields, and thermal state) and intrinsic (e. g., pH, redox potential, and enzymes) stimuli. Leveraging their interaction with the biological system, they hold promise for the evolution of highly effective therapeutic administration systems [3, 4].

Exogenous stimulus-triggered systems

The extrinsic stimulus-triggered system engages drug delivery through external factors like light, ultrasound, magnetic fields, and temperature. This system aims to reduce inter-patient variability by directly applying physical stimuli to the specific tissue for triggering drug release. It offers numerous advantages, enabling controlled and targeted drug release while minimizing side effects on surrounding healthy tissues [5, 6] All the factors are discussed below.

Light-responsive systems

Light-responsive systems represent an extensively explored exogenous system in drug delivery. Electromagnetic radiation with diverse wavelengths, including ultraviolet, visible, and near-infrared light, can modify the structure of light-responsive nanocarriers, thereby enabling controlled drug release at specific locations. The versatility of light as a stimulant from its adaptable nature and high precision, makes it highly applicable for targeted drug delivery and control. Photothermal effects of light, converting it into heat, have been extensively investigated. This concept involves heat generated from light activating heat-sensitive nanocarriers, disrupting their nanostructure by breaking hydrophobic and hydrophilic linkages, thereby facilitating drug release at desired sites. For instance, Li et al. developed nanocarriers equipped with the hydrated moieties AMD3100 and the lipophilic NIR light-to-heat converters IR780 [7]. Guardado-Alvarez et al. capitalized on the high spatial resolution, subcutaneous delivery, and attenuated diffusion properties of NIR radiation to achieve drug release from developed siliceous mesostructured NPs jointly with a disulfide-attached β-cyclodextrin cap. Optical-responsive bio-inert micellar therapeutic delivery systems further underscore the significance of light as a stimulus. The creation of coumarin-modified block copolymers in micelle-drug conjugates demonstrated controlled drug emit of the oncolytic mediator 5-FU under UV irradiation (254 nm) [8]. Peng and colleagues engineered a photo-responsive hydrogel by linking trans-configurated nitrophenyl groups to dextran and pairing it with a cyclodextrin-decorated dextran. Upon exposure to light, the azobenzene is isomerized, causing the release of encapsulated entities. Utilizing Upconverting Nanoparticles (UCNPs), dynamic optically triggered substances can be charged. Xiang et al. developed UCNPs containing an amphipolar di-block copolymer with a UV-responsive lipophilic sphere, releasing drugs under the influence of NIR radiation (wavelength 908 nm), altering the micelle structure due to UV light absorption by the copolymer and inducing disproportion in amphiphilic balance [9-11].

Ultrasound-responsive systems

Ultrasound waves possess thermal, mechanical, and radiation force properties, which contribute to targeted drug release. The medical field widely explores ultrasound technology for imaging-guided drug delivery because of its reliability, parenchyma-penetrating ability, non-intrusion, and precise space-time domination, enabling focused treatment on specific areas [12]. In the exploration of ultrasound potential, an innovative ultrasound-reactive system loaded with doxorubicin was devised employing poly (D, L-lactide-co-glycoside)-methoxy-poly (ethylene glycol) to complex doxorubicin. This system was transformed into stable nanobubbles through boiling. Minimal drug release was observed in the absence of ultrasound exposure [13-15]. Another study focused on Microbubbles (MBs) as ultrasound-enhancing agents carrying mRNA-lipoplexesNPs. Numerous studies have utilized MBs for ultrasound-facilitated gene delivery. For instance, Hossack et al. developed a method utilizing ultrasound-facilitated plasmid DNA delivery from cationic MBs for vascular myocytes. Microbubbles carrying reporter plasmid DNA were sonicated near smooth muscle cells in an in vitro setting using varying acoustic pressures (ranging from 0 to 950 kilopascals) and pulse durations (ranging from 0 to 100 cycles) [16-18].

Magnetic field-responsive system

Recently, magnetically sensitive systems attained considerable cognitive engagement medical field account of advancements in Magnetic Nanoparticles (MNPs) and their application in biomedical and clinical domains. These systems incorporate fabricated metal and superparamagnetic oxide MNPs that exhibit responsiveness to both internal and external stimuli [19, 20]. MNPs play a pivotal role in magnetic-responsive nano-systems due to their biocompatibility and facile synthesis via various techniques such as hydrothermal methods, ignition, thermal decomposition, chemical vapor deposition, and carbon arc, among others. Studies indicate that MNPs, being small with a substantial specific surface area, facilitate cellular activities and signaling for ex vivo and in situ remote control cellular, enabling a promising potential for drug delivery systems [21, 22].

Previously, magnetoactive nanomembrane-based PNIPAAM nanogels and NPs were developed. Results indicated that these membranes were cell-bio-friendly and maintained their modifiable flow characteristics post-45 days of subcutaneous embedding [23]. Various mechanisms, including magneto-driven hyperthermia and directed therapeutic delivery, have been investigated to comprehend magnetic-reactive systems [24]. For further exploration of these mechanisms, Thirunavukkarasu et al. fabricated Superparamagnetic Iron Oxide NPs (SIONPs) for therapeutic applications. In this study, SIONPs and Doxorubicin (DOX) were loaded into a poly (α-hydroxy acids) (PHA) medium, reacting to the thermal effects induced by SIONPs under magnetic field influence, consequently facilitating the release of DOX. Ex-vivo assay demonstrated thermotolerance of the PHA medium, showing approximately 37 °C, drug release reached 39%, while at 45 °C, it increased to 57% [25]. In separate work, Wang et al. developed an implantable chitosan-based hydrogel integrated with magnetic properties, incorporating hydrophobic (rifampicin) and hydrophilic (Adriamycin) medications, exhibiting controlled drug release at targeted sites [26]. Reports indicate that alternative magnetic fields can control the timing and dosage of drug release from nano-formulations. The formulation of Pluronic/poly (ethylene imine) polymeric nanospheres stands as an illustration of an alternative magneto-sensitive system, enabling the triggered delivery of siRNA at targeted sites. Stable nano-sized polyelectrolyte complexes containing anionic siRNA-PEG conjugates facilitated the release of drugs through cleavable disulfide linkages [27]. A study introduced the utilization of triblock copolymer, poly [(acrylic acid)-block-(N-isopropyl acrylamide)-block-(acrylic acid)], in magnetic field-responsive systems. These copolymers, self-assembled into magnetic nanocarriers (SAMNs) by immobilizing amine groups on iron oxides (Fe3O4-NH2), were further grafted with folic acid for additional targeting effects. Encapsulation of the hydrophobic anticancer drug curcumin, into SAMNs resulted in enhanced curcumin release upon exposure to the magnetic field because of the paramagnetic behaviour of SAMNs [29].

Thermal responsive systems

Thermal-responsive systems represent an area of exploration in extrinsic triggered systems within medicinal fields for both intervention and assessment techniques. Tumour sites typically exhibit higher temperatures (40–42 °C) compared to healthy tissues (37 °C). Thus, heat-sensitive nanospheres sustain their load at ambient temperatures and liberate upon exposure to hyperthermia in infected sites [30]. Two primary strategies dominate the exploration of thermo-responsive systems. In the first, drug loaders are synthesized to emit the drug when exposed to hyperthermia. For instance, polycaprolactone (N-isopropyl acrylamide) (PNIPAM) conjugated with nanostructured carbon effectively released drug molecules in response to higher temperatures (40 °C). This resulted in a substantial decrease in impaired cellular functionality was observed at 40 °C, showing a 20% reduction in viability relative to the baseline viability observed at 37 °C following nanotherapeutic intervention. The secondary approach revolves around utilizing pharmaceutical carriers engineered for an immediate or rapid release triggered by elevated temperatures induced via an external stimulus. This trigger initiated a thermo-responsive agent in the vector to generate thermal energy, prompting rapid drug liberation at the intended area [31, 32]. The integration of block polymers in thermo-responsive systems has provided a new area in the pharmaceutical field. Block polymers with thermo-responsive monomers enable the manipulation of the Lower Critical Solution Temperature (LCST) to a desired point. PEG-b-PNIPAAM copolymers formed micelles via Atom Transfer Radical Polymerization (ATRP) when exceeding the thermal threshold. These micelles, comprising PNIPAM-b-PMMA, exhibited enhanced drug liberation upon reaching temperatures beyond the LCST point of 38 °C [33, 34]. The therapeutic efficacy of hydrophobic anti-neoplastic agent Paclitaxel (PTX) was notably enhanced when loaded into nanoparticles, given the formulation's prolonged vascular transit time conditions, with the LCST surpassing normal body temperature [35, 36]. An innovative method using a temperature-responsive macromolecular drug carrier, Elastin-like polypeptide (ELP), effectively localized neoplasms. ELP clusters attached to tumor blood vessels only expose tumors to 41.5 °C heat. Upon returning to febrile temperature, these particles solubilized within the plasma, augmenting vascular density and facilitating increased recanalization of ELPs penetrating neoplastic vascular networks, leading to substantial extravascular accumulation [37-39]. Another approach to achieve thermal responsiveness in drug formulation is through cryotherapy. Zhang et al. fabricated nanospheres with a core-shell loaded with pluronic F127 and chitosan, leveraging their inherent heat-triggered swelling and shrinking characteristic. These nanospheres, when combined with cryotherapy, demonstrated a high permeable barrier and effective encapsulation of small therapeutic agents, showing promise in disease treatment [40-42].

Endogenous stimuli-responsive systems

Biological responses can be elicited through the utilization of endogenous stimuli, including fluctuations in pH levels, variations in tissue-specific enzyme concentrations, and gradients in reduction-oxidation (redox) potentials [43].

Ph-responsive systems

The biological system encompasses distinct pH gradients across various organs, offering an advantage for pH-responsive nanocarriers. These carriers undergo conformational changes or cleavage of pH-responsive bonds at particular pH values, releasing their cargo drugs precisely at the intended site. Hemodynamic and healthy tissues typically maintain a pH of approximately 7.4; conversely, tumor interstitial spaces and inflamed areas have an approximate pH of 6.5. Intracellular organelles like endosomes exhibit a pH of 5–6, while late lysosomes have a pH range of 4–5 [44-47]. Numerous materials exhibit responsiveness to pH stimuli, encompassing both organic and inorganic substances. Recently, dendritic polymers have gained prominence in pH stimuli-responsive systems due to their manipulative properties, including solubility, volume, and conformation [48]. Their biological effectiveness is enhanced when combined with Polyethylene glycol, altering structure, size, and biocompatibility. Moreover, coupling dendritic polymers with antitumor drugs through hydrazine bonds has shown increased effectiveness in cancer treatment [49]. pH-responsive nano-systems have been employed to deliver hydrophobic anticancer drugs to specific sites. For instance, the fabrication of Curcumin (CUR) DOX-loaded polyethylene glycol nanoparticles combined with transferrin (Tf) demonstrated accelerated release of both CUR and DOX in mildly acidic environments, highlighting the pH-dependent drug release in this setup [50]. Another innovative approach engages emergent-organization hyaluronic acid NPs using calcium phosphate to create hydroxyapatite NPs incorporated DOX. These minerals dissolve upon exposure to low pH, thereby releasing the drug at specific tumor sites [51]. Moreover, polymers comprising ionizable clusters, like amines and carbonic acids, show promise in developing pH-responsive nanospheres. Utilizing a PMAA–PMA copolymer significantly enhanced the bioequivalence of cyclosporine A, exhibiting the drug emitted at pH>6, thereby preserving the drug from acid decomposition after passing through the stomach [52]. Ulbrich et al. developed an HPMA (N-(2-hydroxypropyl) methacrylamide) polymer linked utilizing hydrazone groups as pH-triggered linkers for attaching the antineoplastic agent DOX. These conjugates remained stable at pH 7.4 and effectively emit the drug at pH 5. Additionally, they coupled an antibody to the polymer backbone to attain efficient directing of T cell lymphoma EL 4 cells [53-55].

Redox-responsive systems

In our biological system, the extracellular and intracellular spaces exhibit a redox potential difference of approximately ~100–1000 fold, along intercellular environment being oxidative and intracellular being reductive. An emerging paradigm shift in therapeutics involves this redox potential gradient in redox-responsive systems for targeted drug delivery [56]. Redox-sensitive nanocarriers, particularly in gene delivery, offer promising avenues for protecting plasmid DNA or siRNA outside the cell and releasing them upon cellular entry [57]. Recent investigations by Xiao et al. highlighted an oxidation-reduction signaling system using silica nanoparticles conjugated alongside DOX via an amphiphilic peptide, including a disulfide bond. These nanoparticles securely retained the drug DOX, exhibiting minimal escape in blood circulation and normal cells. Intracellularly, rapid and substantial drug release occurred only upon cleavage of the disulfide bond interjacent the nanospheres and the drug due to the redox potential gradient. This system capitalizes on substantial variances in GSH levels amidst tumor cells, the extracellular matrix, and normal cells, resulting in mitigated toxicity and increased tumor selectivity [58]. Similarly, Zhang et al. employed DOX with a PFG polymer, exploring redox-responsive systems extensively by employing a preclinical breast carcinoma prototype. They integrated thioketal, a Reactive Oxygen Species (ROS) potential stimulator for tumor cells, resulting in enhanced intracellular drug delivery via Glutathione (GSH) activation. This redox-responsive nanocarrier exhibited significantly higher drug-loading efficiency, improved stability, and enhanced cellular uptake [59]. Studies have observed that GSH can upset disulfide coupling within NPs in redox-triggered systems [60]. Additionally, Tirelli et al. demonstrated that polysulfide-containing nanocarriers can respond to oxidants present in their surroundings [61].

Enzyme-responsive systems

Enzyme-triggered systems primarily depend on ester hydrolysis by various enzymes within the biological system [64]. Cathepsin B (CTSB) finds extensive use in enzyme-responsive systems for site-specific drug delivery due to its amplification of carcinoma [65]. Tarassoli et al. investigated CTSB for the emission of indocyanine green (ICG) from polyglutamate (PGA) NPs. They developed biodegradable and self-assembled PGA-NPs incorporating ICG, reporting tumour-targeted drug emission and low toxic profile due to CTSB overexpression [66]. Mao and Gan formulated hydrophilic-phobic poly(glycidol-block-ε-caprolactone) (PG-b-PCL) encapsulating a model compound. In addition to lipase, blockage of PCL decreased, suggesting that the enzyme could still split the ester bonds owing to the kinetics of amalgamation and segregation [67, 68]. Moreover, Minko and colleagues linked paclitaxel to PAMAM G4 dendrimers and then succinate. This system released the drug when ester bonds were broken by esterase, exhibiting superior cell toxicity than the unbound moiety [69]. Aimetti et al. investigated a 4-arm PEG norbornene hydrogel using a peptide cross-linker with terminus thiol moiety. Drug release from this system occurred upon contact with human neutrophil elastase [70]. Additionally, Ghavami et al. fabricated Phospholipase-Sensitive Liposomes (PSL) as a drug-delivery system, where liposome degradation was triggered by tumor cell-derived phospholipase A2 (sPLA2). The activation of PNA release by>80% of phospholipase indicated its potential as an agent to release drugs from enzyme-responsive systems [72]. An enzyme-responsive nanomaterial based on an HPMA triblock copolymer was developed, self-assembling into NPs approximately 85 nm in diameter. This system precisely emits the antineoplastic agent paclitaxel in the cancer microenvironment [73].

Multi stimuli-responsive systems

Multi-stimuli triggered systems, capable of responding to two or more distinct stimuli, are garnering significant interest in therapeutic applications. These systems combine stimuli like pH, temperature, redox potential, magnetic fields, and more within the same matrix [74]. They function as intelligent carriers, precisely releasing their payload at targeted sites in controlled amounts [75]. Examples of multi-stimuli responsive systems include pH-redox, photo-magnetic, and thermo-redox combinations [76]. Qian et al. investigated a multi-stimuli system where the outcomes of the principal stimulus served as an auxiliary stimulus to enhance specificity and synergistic efficacy. They developed a conjugated polymeric nanoparticle exposed to light irradiation, resulting in O₂ generation and inducing cellular apoptosis [77]. In a related study, Lu and associates explored a tri-stimuli delivery system (redox/pH/photo-responsive) comprising organo-silica and copper sulfide nanoparticles (DOX-CuS@PMO) cross-linked by thiol bonds. Their biological evaluation using the U87MG human glioblastoma cell line and a glioblastoma mouse model demonstrated enhanced cellular internalization upon mild laser irradiation of DOX-CuS@PMO [78]. Researchers have also employed bi-stimuli systems, where pH and NIR stimulus are used to fabricate hollow mesoporous copper sulfide NPs (HMCuS NPs) loaded with DOX and coated with hyaluronic acid (HA). This system efficiently delivers the payload to tumor sites as the outer layer of DOX-loaded nanoparticles degrades due to hyaluronidase, influenced by pH and NIR. Similarly, the sensitivity of multi-responsive systems to temperature and redox potential has been explored, enabling specific drug release in the tumor microenvironment [79-81].

Section snippets

The key physicochemical parameters of in vivo stimuli-responsive assembly-disassembly

Nanoparticle assemblies and disassemblies play an integral role in nanoparticle functionality, ensuring stability before reaching the target site and subsequently activating their function through assembly or disassembly in situ [82]. This stimuli-responsive assembly-disassembly can lead to unexpected biological outcomes [83]. Recent studies have shown the emerging selective "turn-on" performance of in vivo stimulus-responsive nano-assemblies and disassemblies, demonstrating their potency in various therapeutic conditions, such as tumor treatment. Comprising eco-friendly polymers, triggered groups, and pharmaceutically bio-active molecules, these in vivo stimulus-responsive systems are designed for targeted drug delivery. They energetically react to the intrinsic microenvironment, enhancing therapy efficacy and enabling control over degradation speed and clearance from the body. The strategies for delectable assembly/disassembly mechanisms revolve around corrupting the delicate equilibrium between the entropy and enthalpy of nano-systems upon cellular/extracellular stimuli in target tissues. These stimuli include the acidity of the microenvironment, overexpressed proteins/enzymes, and high levels of reduced GSH and ROS among others. Dynamic nano assembly/disassembly-based drug delivery systems are adaptable structures that change in response to biological microenvironments [85-87]. Researchers are increasingly interested in exploring stimuli-responsive controllable assembly/disassembly strategies to enhance the efficiency of drug-associated nanosystems. Typically, small units are assembled into nanoscale assemblies to achieve tumor accumulation via the Enhanced Permeability and Retention (EPR) effect, minimizing rapid excretion. Upon reaching the complex tumor microenvironment, these triggered nano assemblies undergo disassembly, releasing their inner active substances, thereby enhancing their therapeutic efficacy. Stimulus-responsive modification can also alter the characteristics of nanoparticles, particularly their size and shape, to achieve desired effects in imaging, therapy, and bioelimination. Therefore, a detailed discussion on pH-stimuli-responsive assembly-disassembly, redox-responsive assembly-disassembly, and enzyme-responsive assembly-disassembly is needed [88, 89].

Ph stimuli-responsive assembly-disassembly

The pH conditions within various human body organs, including the blood (pH 7.2–7.4), endosomes (pH 5.0–6.2), and even the tumor interstitial environment (pH 6.5–6.8), can trigger pH-stimuli-triggered assembly-disassembly processes within cells. The design of pH-responsive diagnostic nanosystems primarily relies on the protonation of specific moieties (e. g., amines). These triggers disrupt the hydrophilic-lipophilic balance, resulting in direct drug release at the target site. The wide usage of pH values at the target site serves as a broad-spectrum stimulus, ultimately enhancing pH-stimuli-responsive assembly-disassembly [90, 91]. In tumor therapy, pH-responsive disassembly has shown promise. Molecules of interest encapsulated in pH-triggered amphiphilic polymers aggregate in the hydrophobic core and undergo self-quenching. They are triggered to disassemble into highly fluorescent molecular units within the acidic tumor microenvironment [92]. Distinguishing neoplastic tissues from surrounding healthy tissues can be achieved with high specificity through pH-responsive assembly-disassembly. For instance, glycyrrhizic acid-modified gold nanoparticles assemble at normal tissue pH (pH 7.4) and disassemble at the tumor extracellular pH (pH 6.8), facilitating cellular uptake of the nanoparticles. This reversible pH-stimuli-responsive assembly-disassembly process can enhance Computed Tomography (CT) imaging for tumor therapy [93]. Redox-responsive assembly-disassembly techniques have gained attention due to the differing redox potential between normal and abnormal tissues. Research focuses on redox-sensitive linkers, such as disulfide bonds, which play a crucial role in this strategy [94]. In redox-responsive nanosystems, payload drug release occurs through the reduction of disulfide bonds, breaking the cross-linkers used for assembly, and degrading hydrophilic bonds, leading to disassembly. Advancements in redox-responsive assembly-disassembly involve utilizing Nile red-based amphiphiles bearing redox-cleavable disulfide bonds that exhibit enhanced binding to the system [95]. Disulfide bonds respond differently in the tumor microenvironment, promoting the self-assembly of small units. For instance, Liang and colleagues developed a Cys(StBu)-Lys(Ru(bpy)3 2+)-CBT probe for tumor imaging that self-assembles into Ru(bpy)3 2+NPs within cells under the influence of the redox potential [96]. Enzyme-responsive assembly-disassembly strategies leverage the catalytic activity of endogenous enzymes. Diseases often involve the overexpression of specific enzymes like Alkaline Phosphatase (ALP), matrix metalloproteinases (MMPs), and furin, paving the way for enzyme-responsive assembly-disassembly. Nanoparticles carrying drug payloads reach the target site and release drugs upon catalysis by these overexpressed enzymes, so many stimuli actions with assembly mechanisms and responses are discussed below in table 1 [97]. Drugs combined with enzyme-sensitive linkers, incorporated into amphiphilic polymers, aggregate in the hydrophobic core. Upon contact with specific enzymes overexpressed at the target site, these assemblies disassemble and release the drug [98]. Furthermore, endogenous enzymes are explored to enhance the accumulation of nanoparticles in biological systems, particularly in tumor imaging. Combining tumor probes with in situ enzyme-responsive assembly-disassembly mechanisms can "turn on" tumor-associated enzyme activity, enabling imaging in living cells [99].

Table 1: List of stimuli-responsive assembly and disassembly

ADME (Absorption distribution metabolism excretion) in nano-interaction

The pharmacokinetics of nanoscale formulations differ significantly from those of conventional formulations. Understanding the relationship between drug pharmacokinetics, encompassing absorption, distribution, metabolism, and elimination, and nanoscale preparation is crucial. The impact of characteristics (such as size, surface polarity, charge, and bioadhesive properties) of NPs on ADME profiles is paramount [115].

Size

The size of NPs plays a pivotal role in the formulation of ADME as it influences uptake by enterocytes and M cells within the biological system. Additionally, cellular uptake through the paracellular route depends on NPs size, particularly when the NPs substance inherently enhances transmissivity by opening a permeability barrier [116]. Studies have demonstrated size-dependent absorption mechanisms; for instance, carboxylated chitosan-grafted poly (methyl methacrylate) NPs of varying sizes (300, 600, and 1000 nm) were evaluated in vitro using caco-2 mono-cultures and co-cultures with M cells. Smaller particles exhibited greater transportation through all routes compared to larger NPs. Similar size-dependent ADME trends have been observed in studies with decomposable PLGA NPs using the Caco-2 model [117].

Surface polarity

Surface polarity significantly affects nano-bio interactions and ADME. Enhancing NP stability through surface polarity helps prevent NP aggregation in the gut lumen and may reduce enzymatic degradation [118]. However, increased surface polarity might decrease intestinal permeability [119]. This property is often utilized to reduce protein adsorption on NP surfaces, potentially leading to reduced hepatic clearance [120].

Charge

The charge on NPs affects formulation stability, influencing NPs clustering in the gut lumen and the absorption process. Upon contact with the biological system, the charge density of NPs can undergo alterations [121]. Assimilated into the peripheral circulation, charged NPs, specifically ones, interact with plasma proteins, leading to aggregation. Superiorly charged NPs are likely to exhibit increased accumulation in target tissues [122].

Bioadhesive properties

Bioadhesive NPs impact the ADME process by prolonging the dwell span in the gut and maintaining extended interaction with gut exterior barriers, potentially improving ADME [123-124]. Recent studies have explored the impact of bioadhesive NPs not only on absorption but also on NP distribution within the biological system. For example, attaching a biocompatible layer (poly(butadiene-maleic anhydride-co-L dopa to non-biocompatible Polystyrene (PS) beads resulted in exceptional enhanced cellular intake [125, 126].

Pharmacokinetic (pk) parameter based on nano-bio interaction

The comprehensive analysis of ADME parameters concerning drug-loaded NPs can be challenging due to variations in NP formulations and their interactions within biological systems. ADME data is often confined to Cmax, Tmax, and AUC, with limited research detailed parameters like t_1/2, C, V_dss, or MRT [127]. Sonaje et al. conducted a study investigating the pharmacokinetics, pharmacodynamics (blood glucose), and biodistribution of pH-triggered NPs comprising chitosan and poly(gamma-glutamic acid). The comparison was made between oral and subcutaneous administration in rats using Single-photon Emission Computed Tomography (SPECT). The investigation results revealed that orally given aspart-insulin was incorporated into the peripheral circulation, whereas the nanocarrier was mostly held in the gut following hypodermal administration. Peak aspart-insulin concentration in peripheral tissue/plasma occurred at 20 min post-injection. A comparison of PD/PK profiles between orally administered as part-insulin and SC infusion of NPH-insulin, moderate-acting insulin preparation, suggested the potential of this nano-bio system as a non-invasive alternative for basal insulin regimen [128]. Another study, inspired by this work, focused on hepato-selective agent delivery carriers comprising chitosan/poly (ethylene glycol)–glycyrrhetinic acid NPs. The PK analysis of these NPs was conducted using single-photon emission computed tomography (SPECT), while cellular uptake was assessed using human hepatic carcinoma cells (QGY-7703 cells). Results indicated the remarkable hepato-selective ability of CTS/PEG–GA NPs, maintaining high levels during the experiment, with liver accumulation reaching 51.3% at 3 h post-injection [129].

Two-dimensional (2D) nanomaterials interactions with biological moieties

2D materials refer to substances alongside a thickness of meagernanometres, typically existing as laminate materials with intense in-plane bonds and weak van der Waals-like linkage amidst laminae. These nanomaterials have gained attention in pharmaceuticals derived their unique structural and physiochemical characteristics [130]. Their sheet-like planar morphology, held together by weak van der Waals forces, endows 2D nanomaterials with exceptional optical, electrical, and mechanical properties, elevating their significance [131]. Moreover, their large surface area-to-volume ratio allows the loading of various pharmaceutically active agents onto their surfaces through non-covalent interactions [132, 133]. This high surface tunability enables the design of biocompatible nanomaterials for applications spanning drug delivery, bioimaging, biosensors, stimulus-responsive theranostic agents, and regenerative medicine [134-136]. The interaction of 2D nanomaterials with biomedical systems, encompassing cells, cytoplasmic organelles, and biomolecules, is remarkable due to their large surface areas providing high surface energy and numerous active centers. This enhanced interaction holds potential for numerous healthcare utilization, comprising tissue engineering, additive manufacturing, neoplastic treatment, biosensing, and more [137-139]. Research into new 2D materials and their interactions with biological moieties remains a focal area. Graphene, the ancient identified 2D nanomaterial, finds applications across diverse research fields, comprising therapeutics, sensing, and energy. For instance, graphene oxide (GO), derived from graphene modified with carboxylic acid, epoxide, and hydroxyl groups, exhibits amphiphilic properties and is highly useful in pharmaceutical applications for stabilizing hydrophobic drugs in solution [140-142]. Additionally, reduced graphene oxide (rGO) synthesized via spray drying forms iron oxide-decorated rGO microspheres, displaying synergistic neoplastic treatment. The photothermal properties of rGO enable NIR stimulus, accelerating doxorubicin release and increasing temperature, responding to NIR intensity. Contrasted to 1D or 3D nanomaterials, 2D nanomaterials have the supreme therapeutic application due to their particular surface area, resulting in an abundant quantity of surface atoms compared to volume atoms [143].

Biological applications

In recent times, nanotechnology has emerged as a ground-breaking field impacting pharmaceuticals, materials science, and electronics. Nano-bio interactions in pharmaceuticals have notably advanced with the availability of various nano-based formulations exhibiting superior responses compared to conventional ones. Among these, liposomes stand out as a pivotal carrier system, demonstrating excellent responsiveness to endogenous stimuli like temperature and pH conditions, significantly enhancing therapeutic agent delivery [144-146]. In the field of nanomedicine, exploring nano-bio interfaces remains pivotal for designing safe and effective drug delivery systems, targeting pathological sites, understanding metabolism, and ensuring biocompatibility [147-149]. While the application of nano-bio interactions in pharmaceuticals, especially in drug delivery systems and oral routes, presents numerous advantages, detailed mechanistic studies are imperative to understand the influence of nanoparticles on ADME profiles, thereby enhancing formulation safety and efficacy [150]. Studies by Pascal Ickrath et al. highlighted the impact of nano-bio systems on dermal zinc oxide NPs formulations in human mesenchymal cells, revealing cytotoxicity at elevated doses and genomic instability at average to minimal doses, with prolonged exposure exacerbating cell necrosis impact [151]. Additionally, the work of Luisana Di Cristo et al. delved into nano-bio systems’ role in inhalation therapies delivered via aerosol [152, 153]. Moreover, nano-biosystems play pivotal roles not only in pharmacy but also in biosensing, electronics, and imaging—the vastness of their applications beckons further exploration [154, 155]. This is achieved by controlling drug release within the tumoral vascular and interstitial space, improving liposomal clusters in tumoral tissue through increased blood flow and tumor vasculature penetrability [156]. Responsive drug delivery systems targeting the tumor microenvironment are extensively employed to enhance selectivity in tumor imaging and therapy while minimizing normal cytotoxicity, ultimately elevating therapeutic effectiveness [157, 158]. The development of pH-sensitive dynamic nano assemblies, leveraging upconversion NPs (UCNPs), offers significant therapeutic potential in cancer therapy by capitalizing on the acidic tumor microenvironment the implementation of pH-responsive drug delivery systems facilitates the precise diagnosis of minor orthotopic Hepatocellular Carcinoma (HCC) by functioning as a Magnetic Resonance Imaging (MRI) contrast agent, pivotal for monitoring the progression of cancer [159]. Neurological diseases like Alzheimer’s, Parkinson’s, ALS, Huntington’s disease, epilepsy, and ischemic stroke possess complex, ambiguous pathogenic mechanisms. Current diagnostic methods fall short of meeting clinical demands. Hence, there’s a pressing need for sensitive, specific probes for early diagnosis and therapy. Designing DNDDS offers a new ray of hope in initial assessment, evaluation, and rational treatment of neurological diseases [160, 161]. Tissue injuries and infections often accompany inflammation, recruiting various inflammatory cells and generating ROS. This oxidative stress exacerbates injuries. Additionally, the infected site exhibits a slightly acidic microenvironment. DNDDS designed based on these micro-environmental features alleviates oxidative stress at injured/infected tissues, thereby improving therapeutic efficiency in treating injuries and infections; nano-bio interactions studies play a pivotal role in the pharma industry; some approved products are also enlisted in table 2 [162].

Table 2: Nano-bio responsive approved formulation

Future approach

For future study, so many research problems are still in the way of understanding: The first point is a lack of complete knowledge of the biological mechanisms of nanomaterials. The second point is to effectively use nanomaterials as more intelligent therapeutic and diagnostic modalities, a regulation approach for their catalytic activity needs to be developed. The third point is that the complex environment in vivo must be considered in research on nano-bio interactions. The fourth and last point is more attention should be paid to theoretical simulation to accurately and deeply investigate the nano-bio interactions. Thus, more efforts should be made in the research of nano-bio interactions.

CONCLUSION

If we are heading off to advance nanomedicine, research on the nano-bio interactions of stimuli-based nanomaterials is crucial. This is because drug delivery, metabolism, pathological site targeting, safe and effective nanomedicine, and biocompatibility with minimal side effects all are impacted by nano-bio interactions. We outlined recent developments in nano-bio interactions of nanomaterials in this review. With these developments, nanomaterials will likely play a significant role in biomedicine in the future, particularly in the treatment of cancer-related illnesses.

FUNDING

No funding was received to conduct this study

ABBREVIATIONS

Nanomaterials: NMs, Nanoparticles: NPs, Utilizing Upconverting Nanoparticles: UCNPs, Superparamagnetic Iron Oxide Nano Particles: SIONPs, Doxorubicin: DOX, Self-Assembled into Magnetic Nanocarriers: SAMNs, Lower Critical Solution Temperature: LCST, Atom Transfer Radical Polymerization: ATRP, Paclitaxel: PTX, Elastin-Like Polypeptide: ELP, Curcumin: CUR, Glutathione: GSH, Reactive Oxygen Species: ROS, Cathepsin B: CTSB, Phospholipase-Sensitive Liposomes: PSL, Enhanced Permeability and Retention: EPR, Computed Tomography: CT, Alkaline Phosphatase: ALP, Polystyrene: PS, Single-Photon Emission Computed Tomography: SPECT, Hepatocellular Carcinoma: HCC, Magnetic Resonance Imaging: MRI

AUTHORS CONTRIBUTIONS

Poonam Joshi-Conceptualization, Writing–Original draft, Jyotsana Suyal-Data Curation, Writing–Review, Dr. Tarun Parashar-Supervision, Editing, Shivani Rawat-Editing, review-Writing.

CONFLICT OF INTERESTS

The authors declare no competing interest

REFERENCES

1. Zhang Z, Zhang D, Wei L, Wang X, Xu Y, Li HW. Temperature responsive fluorescent polymer nanoparticles (TRFNPs) for cellular imaging and controlled releasing of drug to living cells. Colloids Surf B Biointerfaces. 2017 Nov;159:905-12. doi: 10.1016/j.colsurfb.2017.08.060, PMID 28898952.

2. Raza A, Hayat U, Rasheed T, Bilal M, Iqbal HM. Smart materials based near-infrared light responsive drug delivery systems for cancer treatment: a review. J Mater Res Technol. 2019;8(1):1497-509. doi: 10.1016/j.jmrt.2018.03.007.

3. Xiang J, Tong X, Shi F, Yan Q, Yu B, Zhao Y. Near-infrared light triggered drug release from UV-responsive diblock copolymer coated up conversion nanoparticles with high monodispersity. J Mater Chem B. 2018;6(21):3531-40. doi: 10.1039/c8tb00651b, PMID 32254448.

4. Mavuso S, Choonara YE, Marimuthu T, Kumar P, Du Toit LC, Kondiah PP. A dual pH/Redox responsive copper ligand nanoliposome bioactive complex for the treatment of chronic inflammation. Int J Pharm. 2016;509(1-2):348-59. doi: 10.1016/j.ijpharm.2016.05.069, PMID 27269194.

5. Li H, Yang X, Zhou Z, Wang K, Li C, Qiao H. Near infrared light triggered drug release from a multiple lipid carrier complex using an all-in-one strategy. J Control Release. 2017 Sep 10;261:126-37. doi: 10.1016/j.jconrel.2017.06.029, PMID 28666728.

6. Jin Q, Mitschang F, Agarwal S. Biocompatible drug delivery system for photo-triggered controlled release of 5-fluorouracil. Biomacromolecules. 2011;12(10):3684-91. doi: 10.1021/bm2009125, PMID 21863834.

7. Peng K, Tomatsu I, Kros A. Light controlled protein release from a supramolecular hydrogel. Chem Commun (Camb). 2010;46(23):4094-6. doi: 10.1039/c002565h, PMID 20464018.

8. Gwon K, Jo EJ, Sahu A, Lee JY, Kim MG, Tae G. Improved near infrared mediated hydrogel formation using diacrylated pluronic F127-coated upconversion nanoparticles. Mater Sci Eng C Mater Biol Appl. 2018 Sep 1;90:77-84. doi: 10.1016/j.msec.2018.04.029, PMID 29853148.

9. Yi C, Yu Z, Ren Q, Liu X, Wang Y, Sun X. Nanoscale ZnO based photosensitizers for photodynamic therapy. Photodiagnosis Photodyn Ther. 2020 Jun;30:101694. doi: 10.1016/j.pdpdt.2020.101694, PMID 32109615.

10. Li Q, Li W, Di H, Luo L, Zhu C, Yang J. A photosensitive liposome with NIR light triggered doxorubicin release as a combined photodynamic chemo therapy system. J Control Release. 2018 May;277:114-25. doi: 10.1016/j.jconrel.2018.02.001, PMID 29408424.

11. Luo Z, Jin K, Pang Q, Shen S, Yan Z, Jiang T. On-demand drug release from dual-targeting small nanoparticles triggered by high intensity focused ultrasound enhanced glioblastoma targeting therapy. ACS Appl Mater Interfaces. 2017;9(37):31612-25. doi: 10.1021/acsami.7b10866, PMID 28861994.

12. De Cock I, Lajoinie G, Versluis M, De Smedt SC, Lentacker I. Sonoprinting and the importance of microbubble loading for the ultrasound mediated cellular delivery of nanoparticles. Biomaterials. 2016 Mar;83:294-307. doi: 10.1016/j.biomaterials.2016.01.022, PMID 26796042.

13. Dewitte H, Vanderperren K, Haers H, Stock E, Duchateau L, Hesta M. Theranostic mRNA loaded microbubbles in the lymphatics of dogs: implications for drug delivery. Theranostics. 2015;5(1):97-109. doi: 10.7150/thno.10298, PMID 25553101.

14. Paris JL, Manzano M, Cabanas MV, Vallet Regi M. Mesoporous silica nanoparticles engineered for ultrasound-induced uptake by cancer cells. Nanoscale. 2018;10(14):6402-8. doi: 10.1039/C8NR00693H, PMID 29561558.

15. Papa AL, Korin N, Kanapathipillai M, Mammoto A, Mammoto T, Jiang A. Ultrasound sensitive nanoparticle aggregates for targeted drug delivery. Biomaterials. 2017 Sep;139:187-94. doi: 10.1016/j.biomaterials.2017.06.003, PMID 28618348.

16. Hosseini Nassab N, Samanta D, Abdolazimi Y, Annes JP, Zare RN. Electrically controlled release of insulin using polypyrrole nanoparticles. Nanoscale. 2017;9(1):143-9. doi: 10.1039/c6nr08288b, PMID 27929180.

17. Phillips LC, Klibanov AL, Wamhoff BR, Hossack JA. Targeted gene transfection from microbubbles into vascular smooth muscle cells using focused ultrasound-mediated delivery. Ultrasound Med Biol. 2010;36(9):1470-80. doi: 10.1016/j.ultrasmedbio.2010.06.010, PMID 20800174.

18. Yang HY, Li Y, Lee DS. Multifunctional and stimuli-responsive magnetic nanoparticle-based delivery systems for biomedical applications. Advanced Therapeutics. 2018;1(2):1800011. doi: 10.1002/adtp.201800011.

19. Su FY, Chen J, Son HN, Kelly AM, Convertine AJ, West TE. Polymer-augmented liposomes enhancing antibiotic delivery against intracellular infections. Biomater Sci. 2018;6(7):1976-85. doi: 10.1039/c8bm00282g, PMID 29850694.

20. Hoare T, Santamaria J, Goya Gf V. Iron oxide loaded nanotheranostics: major obstacles to in vivo studies and clinical translation. J Control Release. 2009;198(10):35-54.

21. Zhou X, Wang L, Xu Y, Du W, Cai X, Wang F. A pH and magnetic dual response hydrogel for synergistic chemo magnetic hyperthermia tumor therapy. RSC Adv. 2018;8(18):9812-21. doi: 10.1039/c8ra00215k, PMID 35540837.

22. Wang Y, Li B, Xu F, Han Z, Wei D, Jia D. Tough magnetic chitosan hydrogel nanocomposites for remotely stimulated drug release. Biomacromolecules. 2018;19(8):3351-60. doi: 10.1021/acs.biomac.8b00636, PMID 29995388.

23. Lee K, Bae KH, Lee Y, Lee SH, Ahn CH, Park TG. Pluronic/polyethylenimine shell crosslinked nanocapsules with embedded magnetite nanocrystals for magnetically triggered delivery of siRNA. Macromol Biosci. 2010;10(3):239-45. doi: 10.1002/mabi.200900291, PMID 19924685.

24. Zhu Y, Tao C, Sanchez Moreno P. DNA capped Fe₃O₄/SiO₂ magnetic mesoporous silica nanoparticles for potential controlled drug release and hyperthermia. Recent Adv Synth Biomed Appl Nanomater. 2015;5:29. doi: 10.1039/C5RA00701A.

25. Khoee S, Karimi MR. Dual drug-loaded Janus graphene oxide based thermoresponsive nanoparticles for targeted therapy. Polymer. 2018 Apr 25;142:80-98. doi: 10.1016/j.polymer.2018.03.022.

26. Yang J, Zhai S, Qin H, Yan H, Xing D, Hu X. NIR controlled morphology transformation and pulsatile drug delivery based on multifunctional phototheranostic nanoparticles for photoacoustic imaging guided photothermal-chemotherapy. Biomaterials. 2018 Sep;176:1-12. doi: 10.1016/j.biomaterials.2018.05.033, PMID 29842986.

27. Aathimanikandan SV, Savariar EN, Thayumanavan S. Temperature sensitive dendritic micelles. J Am Chem Soc. 2005;127(42):14922-9. doi: 10.1021/ja054542y, PMID 16231948.

28. Li Y, Pan S, Zhang W, Du Z. Novel thermo sensitive core-shell nanoparticles for targeted paclitaxel delivery. Nanotechnology. 2009;20(6):065104. doi: 10.1088/0957-4484/20/6/065104, PMID 19417372.

29. Haba Y, Kojima C, Harada A, Kono K. Comparison of thermosensitive properties of poly(amidoamine) dendrimers with peripheral N-isopropylamide groups and linear polymers with the same groups. Angew Chem Int Ed Engl. 2007;46(1-2):234-7. doi: 10.1002/anie.200603346, PMID 17124702.

30. Liu YY, Shao YH, Lu J. Preparation properties and controlled release behaviors of pH-induced thermosensitive amphiphilic gels. Biomaterials. 2006;27(21):4016-24. doi: 10.1016/j.biomaterials.2006.02.042, PMID 16563494.

31. Dreher MR, Liu W, Michelich CR, Dewhirst MW, Chilkoti A. Data from thermal cycling enhances the accumulation of a temperature-sensitive biopolymer in solid tumors. Cancer Res. 2007 May 1;67(9):4418-24. doi: 10.1158/0008-5472.CAN-06-4444.

32. Carmona Moran CA, Zavgorodnya O, Penman AD, Kharlampieva E, Bridges SL JR, Hergenrother RW. Development of gellan gum containing formulations for transdermal drug delivery: component evaluation and controlled drug release using temperature-responsive nanogels. Int J Pharm. 2016;509(1-2):465-76. doi: 10.1016/j.ijpharm.2016.05.062, PMID 27260133.

33. Gao Y, Chan Cu, Gu Q, Lin X, Zhang W, Yeo Dc. Controlled nanoparticle release from stable magnetic microbubble oscillations. NPG Asia Mater. 2016;8(4):e260, doi: 10.1038/am.2016.37.

34. Said SS, Campbell S, Hoare T. Externally addressable smart drug delivery vehicles: current technologies and future directions. Chem Mater. 2019;31(14):4971-89. doi: 10.1021/acs.chemmater.9b01798.

35. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 1989;49(16):4373-84. PMID 2545340.

36. Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T. Acidic extracellular microenvironment and cancer. Cancer Cell Int. 2013;13(1):89. doi: 10.1186/1475-2867-13-89, PMID 24004445.

37. Gerweck LE, Seetharaman K. Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res. 1996;56(6):1194-8. PMID 8640796.

38. Ohkuma S, Poole B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci USA. 1978;75(7):3327-31. doi: 10.1073/pnas.75.7.3327, PMID 28524.

39. Pan D, She W, Guo C, Luo K, Yi Q, Gu Z. Pegylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy. Biomaterials. 2014;35(38):10080-92. doi: 10.1016/j.biomaterials.2014.09.006, PMID 25263685.

40. Cui T, Zhang S, Sun H. Co-delivery of doxorubicin and pH-sensitive curcumin prodrug by transferring targeted nanoparticles for breast cancer treatment. Oncol Rep. 2017;37(2):1253-60. doi: 10.3892/or.2017.5345, PMID 28075466.

41. Han HS, Lee J, Kim HR, Chae SY, Kim M, Saravanakumar G. Robust PEGylated hyaluronic acid nanoparticles as the carrier of doxorubicin: mineralization and its effect on tumor targetability in vivo. J Control Release. 2013;168(2):105-14. doi: 10.1016/j.jconrel.2013.02.022, PMID 23474029.

42. Dai J, Nagai T, Wang X, Zhang T, Meng M, Zhang Q. pH-sensitive nanoparticles for improving the oral bioavailability of cyclosporine a. Int J Pharm. 2004 Aug;280(1-2):229-40. doi: 10.1016/j.ijpharm.2004.05.006, PMID 15265562.

43. Ulbrich K, Etrych T, Chytil P, Jelinkova M, Rihova B. Antibody targeted polymer-doxorubicin conjugates with pH-controlled activation. J Drug Target. 2004;12(8):477-89. doi: 10.1080/10611860400011869, PMID 15621674.

44. Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed Engl. 2003;42(38):4640-3. doi: 10.1002/anie.200250653, PMID 14533151.

45. Bae Y, Kataoka K. Intelligent polymeric micelles from functional poly(ethylene glycol) poly(amino acid) block copolymers. Adv Drug Deliv Rev. 2009;61(10):768-84. doi: 10.1016/j.addr.2009.04.016, PMID 19422866.

46. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001;30(11):1191-212. doi: 10.1016/s0891-5849(01)00480-4, PMID 11368918.

47. Mintzer MA, Simanek EE. Nonviral vectors for gene delivery. Chem Rev. 2009;109(2):259-302. doi: 10.1021/cr800409e, PMID 19053809.

48. Xiao D, Jia HZ, Ma N, Zhuo RX, Zhang XZ. A redox-responsive mesoporous silica nanoparticle capped with amphiphilic peptides by self-assembly for cancer-targeting drug delivery. Nanoscale. 2015;7(22):10071-7. doi: 10.1039/c5nr02247a, PMID 25978679.

49. Zhang Y, Guo Q, An S, Lu Y, Li J, He X. ROS switchable polymeric nanoplatform with stimuli-responsive release for active targeted drug delivery to breast cancer. ACS Appl Mater Interfaces. 2017;9(14):12227-40. doi: 10.1021/acsami.6b16815, PMID 28350451.

50. Jhaveri AM, Torchilin VP. Multifunctional polymeric micelles for delivery of drugs and siRNA. Front Pharmacol. 2014 Apr 25;5:77. doi: 10.3389/fphar.2014.00077, PMID 24795633.

51. Ren H, Wu Y, Ma N, Xu H, Zhang X. Side chain selenium-containing amphiphilic block copolymers: redox controlled self assembly and disassembly. Soft Matter. 2012;8(5):1460-6. doi: 10.1039/C1SM06673K.

52. Oba M, Vachutinsky Y, Miyata K, Kano MR, Ikeda S, Nishiyama N. Antiangiogenic gene therapy of solid tumor by systemic injection of polyplex micelles loading plasmid DNA encoding soluble flt-1. Mol Pharm. 2010;7(2):501-9. doi: 10.1021/mp9002317, PMID 20178335.

53. Liberti MV, Locasale JW. Correction to: the warburg effect: how does it benefit cancer cells. Trends Biochem Sci. 2016;41(3):287. doi: 10.1016/j.tibs.2016.01.004, PMID 29482833.

54. Calderon M, Welker P, Licha K, Graeser R, Kratz F, Haag R. Development of efficient macromolecular prodrugs derived from dendritic polyglycerol. J Control Release. 2010;148(1):e24-5. doi: 10.1016/j.jconrel.2010.07.036, PMID 21529602.

55. Gong F, Peng X, Luo C, Shen G, Zhao C, Zou L. Cathepsin B as a potential prognostic and therapeutic marker for human lung squamous cell carcinoma. Mol Cancer. 2013;12(1):125. doi: 10.1186/1476-4598-12-125, PMID 24139065.

56. Tarassoli SP, De Pinillos Bayona AM, Pye H, Mosse CA, Callan JF, Mac Robert A. Cathepsin B-degradable NIR responsive nanoparticulate platform for target specific cancer therapy. Nanotechnology. 2017;28(5):055101. doi: 10.1088/1361-6528/28/5/055101, PMID 28029105.

57. Mao J, Gan Z. The influence of pendant hydroxyl groups on enzymatic degradation and drug delivery of amphiphilic poly [glycidol-block-(epsilon-caprolactone)] copolymers. Macromol Biosci. 2009;9(11):1080-9. doi: 10.1002/mabi.200900104, PMID 19634151.

58. Calderon M, Graeser R, Kratz F, Haag R. Development of enzymatically cleavable prodrugs derived from dendritic polyglycerol. Bioorg Med Chem Lett. 2009;19(14):3725-8. doi: 10.1016/j.bmcl.2009.05.058, PMID 19553109.

59. Khandare Jj, Jayant S, Singh A, Chandna P, Wang Y, Vorsa N. Dendrimer versus linear conjugate: influence of polymeric architecture on the delivery and anticancer effect of paclitaxel. Bioconjug Chem. 2006;17(6):1464-72. doi: 10.1021/bc060240p, PMID 17105225.

60. Aimetti AA, Machen AJ, Anseth KS. Poly(ethylene glycol) hydrogels formed by thiol-ene photopolymerization for enzyme responsive protein delivery. Biomaterials. 2009;30(30):6048-54. doi: 10.1016/j.biomaterials.2009.07.043, PMID 19674784.

61. Zhao C, Zhuang X, He P, Xiao C, He C, Sun J. Synthesis of biodegradable thermo- and pH-responsive hydrogels for controlled drug release. Polymer. 2009;50(18):4308-16. doi: 10.1016/j.polymer.2009.07.010.

62. Thamphiwatana S, Gao W, Pornpattananangkul D, Zhang Q, Fu V, Li J. Phospholipase A2-responsive antibiotic delivery via nanoparticle stabilized liposomes for the treatment of bacterial infection. J Mater Chem B. 2014;2(46):8201-7. doi: 10.1039/C4TB01110D, PMID 25544886.

63. Cai H, Wang X, Zhang H, Sun L, Pan D, Gong Q. Enzyme sensitive biodegradable and multifunctional polymeric conjugate as theranostic nanomedicine. Appl Mater Today. 2018 Jun;11:207-18. doi: 10.1016/j.apmt.2018.02.003.

64. Lei B, Chen M, Wang Y, Zhang J, Xu S, Liu H. Double security drug delivery system DDS constructed by multi-responsive (pH/redox/US) microgel. Colloids Surf B Biointerfaces. 2020;193:111022. doi: 10.1016/j.colsurfb.2020.111022, PMID 32416517.

65. Guragain S, Bastakoti BP, Malgras V, Nakashima K, Yamauchi Y. Multi stimuli-responsive polymeric materials. Chemistry. 2015;21(38):13164-74. doi: 10.1002/chem.201501101, PMID 26219746.

66. Wang L, Liu L, Dong B, Zhao H, Zhang M, Chen W. Multi stimuli responsive biohybrid nanoparticles with cross-linked albumin coronae self-assembled by a polymer protein biodynamer. Acta Biomater. 2017;54:259-70. doi: 10.1016/j.actbio.2017.03.009, PMID 28286038.

67. Qian C, Yu J, Chen Y, Hu Q, Xiao X, Sun W. Light-activated hypoxia responsive nanocarriers for enhanced anticancer therapy. Adv Mater. 2016;28(17):3313-20. doi: 10.1002/adma.201505869, PMID 26948067.

68. Lu N, Huang P, Fan W, Wang Z, Liu Y, Wang S. Tri-stimuli responsive biodegradable theranostics for mild hyperthermia enhanced chemotherapy. Biomaterials. 2017;126:39-48. doi: 10.1016/j.biomaterials.2017.02.025, PMID 28254692.

69. Hegazy M, Zhou P, Wu G, Wang L, Rahoui N, Taloub N. Construction of polymer coated core-shell magnetic mesoporous silica nanoparticles with triple responsive drug delivery. Polym Chem. 2017;8(38):5852-64. doi: 10.1039/C7PY01179B.

70. Feng Q, Zhang Y, Zhang W, Shan X, Yuan Y, Zhang H. Tumor targeted and multi-stimuli responsive drug delivery system for near-infrared light-induced chemo-phototherapy and photoacoustic tomography. Acta Biomater. 2016;38:129-42. doi: 10.1016/j.actbio.2016.04.024, PMID 27090593.

71. Li F, Lu J, Kong X, Hyeon T, Ling D. Dynamic nanoparticle assemblies for biomedical applications. Adv Mater. 2017 Apr;29:14. doi: 10.1002/adma.201605897, PMID 28224677.

72. Rabiee N, Yaraki MT, Garakani SM, Garakani SM, Ahmadi S, Lajevardi A. Recent advances in porphyrin based nanocomposites for effective targeted imaging and therapy. Biomaterials. 2020 Feb;232:119707. doi: 10.1016/j.biomaterials.2019.119707, PMID 31874428.

73. Li F, Qin Y, Lee J, Liao H, Wang N, Davis TP. Stimuli-responsive nano assemblies for remotely controlled drug delivery. J Control Release. 2020 Jun 10;322:566-92. doi: 10.1016/j.jconrel.2020.03.051, PMID 32276006.

74. Low LE, Wu J, Lee J, Tey BT, Goh BH, Gao J. Tumor responsive dynamic nanoassemblies for targeted imaging therapy and microenvironment manipulation. J Control Release. 2020 Aug 10;324:69-103. doi: 10.1016/j.jconrel.2020.05.014, PMID 32423874.

75. Hirsjarvi S, Sancey L, Dufort S, Belloche C, Vanpouille Box C, Garcion E. Effect of particle size on the biodistribution of lipid nanocapsules: comparison between nuclear and fluorescence imaging and counting. Int J Pharm. 2013;453(2):594-600. doi: 10.1016/j.ijpharm.2013.05.057, PMID 23747436.

76. Yuan Y, Zhang CJ, Kwok RT, Mao D, Tang BZ, Liu B. Light up probe based on AIE gens: dual signal turn on for caspase cascade activation monitoring. Chem Sci. 2017;8(4):2723-8. doi: 10.1039/c6sc04322d, PMID 28553507.

77. Webb BA, Chimenti M, Jacobson MP, Barber DL. Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer. 2011;11(9):671-7. doi: 10.1038/nrc3110, PMID 21833026.

78. Harris RJ, Cloughesy TF, Liau LM, Prins RM, Antonios JP, Li D. pH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI. Neuro Oncol. 2015;17(11):1514-24. doi: 10.1093/neuonc/nov106, PMID 26113557.

79. Darwich Z, Klymchenko AS, Dujardin D, Mely Y. Imaging lipid order changes in endosome membranes of live cells by using a nile red-based membrane probe. RSC Adv. 2014;4(17):8481-8. doi: 10.1039/C3RA47181K.

80. Dou Y, Guo Y, Li X, Li X, Wang S, Wang L. Size tuning ionization to optimize gold nanoparticles for simultaneous enhanced CT imaging and radiotherapy. ACS Nano. 2016;10(2):2536-48. doi: 10.1021/acsnano.5b07473, PMID 26815933.

81. Karimi M, Ghasemi A, Sahandi Zangabad P, Rahighi R, Moosavi Basri SM, Mirshekari H. Smart micro/nanoparticles in stimulus responsive drug/gene delivery systems. Chem Soc Rev. 2016;45(5):1457-501. doi: 10.1039/c5cs00798d, PMID 26776487.

82. Niko Y, Arntz Y, Mely Y, Konishi GI, Klymchenko AS. Disassembly driven fluorescence turn on of polymerized micelles by reductive stimuli in living cells. Chemistry. 2014;20(50):16473-7. doi: 10.1002/chem.201405040, PMID 25347980.

83. Li J, Hai Z, Xiao H, Yi X, Liang G. Intracellular self assembly of Ru(bpy)³²⁺ nanoparticles enables persistent phosphorescence imaging of tumors. Chem Commun (Camb). 2018;54(28):3460-3. doi: 10.1039/C8CC01759J, PMID 29560995.

84. Li H, Wang P, Deng Y, Zeng M, Tang Y, Zhu WH. Combination of active targeting enzyme triggered release and fluorescent dye into gold nanoclusters for endomicroscopy guided photothermal/photodynamic therapy to pancreatic ductal adenocarcinoma. Biomaterials. 2017 Sep;139:30-8. doi: 10.1016/j.biomaterials.2017.05.030, PMID 28582716.

85. Chien MP, Carlini AS, Hu D, Barback CV, Rush AM, Hall DJ. Enzyme-directed assembly of nanoparticles in tumors monitored by in vivo whole animal imaging and ex vivo super-resolution fluorescence imaging. J Am Chem Soc. 2013;135(50):18710-3. doi: 10.1021/ja408182p, PMID 24308273.

86. Ma X, Wang Y, Zhao T, Li Y, Su LC, Wang Z. Ultra pH sensitive nanoprobe library with broad pH tunability and fluorescence emissions. J Am Chem Soc. 2014;136(31):11085-92. doi: 10.1021/ja5053158, PMID 25020134.

87. Yu J, He X, Wang Z, Liu S, Hao D, Li X. Combination of starvation therapy and Pt-NP based chemotherapy for synergistic cancer treatment. J Mater Chem B. 2021;9(32):6406-11. doi: 10.1039/d1tb01222c, PMID 34318860.

88. Gao X, Yue Q, Liu Z, Ke M, Zhou X, Li S. Guiding brain tumor surgery via blood-brain barrier permeable gold nanoprobes with acid triggered MRI/SERRS signals. Adv Mater. 2017 Jun;29:21. doi: 10.1002/adma.201603917, PMID 28295679.

89. Park H, Kim J, Jung S, Kim WJ. DNA AU nanomachine equipped with i‐motif and G‐quadruplex for triple combinatorial anti‐tumor therapy. Adv Funct Materials. 2018;28(5):1705416. doi: 10.1002/adfm.201705416.

90. Chuan X, Song Q, Lin J, Chen X, Zhang H, Dai W. Novel free paclitaxel loaded redox responsive nanoparticles based on a disulfide-linked poly (ethylene glycol)-drug conjugate for intracellular drug delivery: synthesis characterization and antitumor activity in vitro and in vivo. Mol Pharm. 2014;11(10):3656-70. doi: 10.1021/mp500399j, PMID 25208098.

91. ReferencesKoo AN, Min KH, Lee HJ, Lee SU, Kim K, Kwon IC. Tumor accumulation and antitumor efficacy of docetaxel loaded core shell corona micelles with shell-specific redox responsive cross links. Biomaterials. 2012;33(5):1489-99. doi: 10.1016/j.biomaterials.2011.11.013, PMID 22130564.

92. Zhang Z, Yin L, Tu C, Song Z, Zhang Y, Xu Y. Redox responsive core cross-linked polyester micelles. ACS Macro Lett. 2013;2(1):40-4. doi: 10.1021/mz300522n, PMID 23536920.

93. Li L, Fu S, Chen C, Wang X, Fu C, Wang S. Microenvironment driven bioelimination of magnetoplasmonic nanoassemblies and their multimodal imaging guided tumor photothermal therapy. ACS Nano. 2016;10(7):7094-105. doi: 10.1021/acsnano.6b03238, PMID 27309678.

94. Purcell BP, Lobb D, Charati MB, Dorsey SM, Wade RJ, Zellars KN. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat Mater. 2014;13(6):653-61. doi: 10.1038/nmat3922, PMID 24681647.

95. Gallo J, Kamaly N, Lavdas I, Stevens E, Nguyen QD, Wylezinska Arridge M. CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging. Angew Chem Int Ed Engl. 2014;53(36):9550-4. doi: 10.1002/anie.201405442, PMID 25045009.

96. Huang P, Gao Y, Lin J, Hu H, Liao HS, Yan X. Tumor-specific formation of enzyme instructed supramolecular self-assemblies as cancer theranostics. ACS Nano. 2015;9(10):9517-27. doi: 10.1021/acsnano.5b03874, PMID 26301492.

97. He C, Yin L, Tang C, Yin C. Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs. Biomaterials. 2012;33(33):8569-78. doi: 10.1016/j.biomaterials.2012.07.063, PMID 22906606.

98. Verma MS, Liu S, Chen YY, Meerasa A, Gu FX. Size tunable nanoparticles composed of dextran-b-poly(D, L-lactide) for drug delivery applications. Nano Res. 2012;5(1):49-61. doi: 10.1007/s12274-011-0184-z.

99. Gaumet M, Gurny R, Delie F. Localization and quantification of biodegradable particles in an intestinal cell model: the influence of particle size. Eur J Pharm Sci. 2009;36(4-5):465-73. doi: 10.1016/j.ejps.2008.11.015, PMID 19124077.

100. Pawar VK, Meher JG, Singh Y, Chaurasia M, Surendar Reddy B, Chourasia MK. Targeting of gastrointestinal tract for amended delivery of protein/peptide therapeutics: strategies and industrial perspectives. J Control Release. 2014;196:168-83. doi: 10.1016/j.jconrel.2014.09.031, PMID 25305562.

101. Xu Q, Ensign LM, Boylan NJ, Schon A, Gong X, Yang JC. Impact of surface polyethylene glycol (PEG) density on biodegradable nanoparticle transport in mucus ex vivo and distribution in vivo. ACS Nano. 2015;9(9):9217-27. doi: 10.1021/acsnano.5b03876, PMID 26301576.

102. Guo J, Bourre L, Soden DM, O Sullivan GC, O Driscoll C. Can non viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics? Biotechnol Adv. 2011;29(4):402-17. doi: 10.1016/j.biotechadv.2011.03.003, PMID 21435387.

103. Bourganis V, Karamanidou T, Samaridou E, Karidi K, Kammona O, Kiparissides C. On the synthesis of mucus permeating nanocarriers. Eur J Pharm Biopharm. 2015;97(A):239-49. doi: 10.1016/j.ejpb.2015.01.021, PMID 25661586.

104. Guo J, Fisher KA, Darcy R, Cryan JF, O Driscoll C. Therapeutic targeting in the silent era: advances in non-viral siRNA delivery. Mol Biosyst. 2010;6(7):1143-61. doi: 10.1039/c001050m, PMID 20431817.

105. Prego C, Fabre M, Torres D, Alonso MJ. Efficacy and mechanism of action of chitosan nanocapsules for oral peptide delivery. Pharm Res. 2006;23(3):549-56. doi: 10.1007/s11095-006-9570-8, PMID 16525861.

106. Huang Y, Leobandung W, Foss A, Peppas NA. Molecular aspects of muco and bioadhesion. J Control Release. 2000;65(1-2):63-71. doi: 10.1016/S0168-3659(99)00233-3.

107. Reineke J, Cho DY, Dingle YL, Cheifetz P, Laulicht B, Lavin D. Can bioadhesive nanoparticles allow for more effective particle uptake from the small intestine? J Control Release. 2013;170(3):477-84. doi: 10.1016/j.jconrel.2013.05.043, PMID 23796432.

108. Fan T, Chen C, Guo H, Xu J, Zhang J, Zhu X. Design and evaluation of solid lipid nanoparticles modified with peptide ligand for oral delivery of protein drugs. Eur J Pharm Biopharm. 2014;88(2):518-28. doi: 10.1016/j.ejpb.2014.06.011, PMID 24968819.

109. Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (Lond). 2008;3(5):703-17. doi: 10.2217/17435889.3.5.703, PMID 18817471.

110. Sonaje K, Lin KJ, Wey SP, Lin CK, Yeh TH, Nguyen HN. Biodistribution pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: oral delivery using pH-responsive nanoparticles vs. subcutaneous injection. Biomaterials. 2010;31(26):6849-58. doi: 10.1016/j.biomaterials.2010.05.042, PMID 20619787.

111. Tian Q, Zhang CN, Wang XH, Wang W, Huang W, Cha RT. Glycyrrhetinic acid-modified chitosan/poly(ethylene glycol) nanoparticles for liver targeted delivery. Biomaterials. 2010;31(17):4748-56. doi: 10.1016/j.biomaterials.2010.02.042, PMID 20303163.

112. Konwarh R, Karak N, Rai SK, Mukherjee AK. Polymer-assisted iron oxide magnetic nanoparticle immobilized keratinase. Nanotechnology. 2009;20(22):225107. doi: 10.1088/0957-4484/20/22/225107, PMID 19433867.

113. Yang Z, Lu Y, Yang Z. ChemInform abstract: mesoporous materials: tunable structure morphology and composition. ChemInform. 2009;40:27. doi: 10.1002/chin.200927203.

114. Aghili Z, Taheri S, Zeinabad HA, Pishkar L, Saboury AA, Rahimi A. Investigating the interaction of Fe nanoparticles with lysozyme by biophysical and molecular docking studies. Plos One. 2016;11(10):e0164878. doi: 10.1371/journal.pone.0164878, PMID 27776180.

115. You CC, Agasti SS, De M, Knapp MJ, Rotello VM. Modulation of the catalytic behavior of α-chymotrypsin at monolayer-protected nanoparticle surfaces. 2006 Nov 15;128:14612-8. doi: 10.1021/ja064433z.

116. Bera S, Dhar J, Dasgupta R, Basu G, Chakraborti S, Chakrabarti P. Molecular features of interaction involving hen egg white lysozyme immobilized on graphene oxide and the effect on activity. Int J Biol Macromol. 2018;120(B):2390-8. doi: 10.1016/j.ijbiomac.2018.09.007, PMID 30218729.

117. Novoselov KS, Geim AK, Morozov SV, Jiang D, Zhang Y, Dubonos SV. Electric field effect in atomically thin carbon films. Science. 2004;306(5696):666-9. doi: 10.1126/science.1102896, PMID 15499015.

118. Xu M, Liang T, Shi M, Chen H. Graphene like two-dimensional materials. Chem Rev. 2013;113(5):3766-98. doi: 10.1021/cr300263a, PMID 23286380.

119. Georgakilas V, Tiwari JN, Kemp KC, Perman JA, Bourlinos AB, Kim KS. Noncovalent functionalization of graphene and graphene oxide for energy materials biosensing catalytic and biomedical applications. Chem Rev. 2016;116(9):5464-519. doi: 10.1021/acs.chemrev.5b00620, PMID 27033639.

120. Ghosal K, Sarkar K. Biomedical applications of graphene nanomaterials and beyond. ACS Biomater Sci Eng. 2018;4(8):2653-703. doi: 10.1021/acsbiomaterials.8b00376, PMID 33434995.

121. Manzeli S, Ovchinnikov D, Pasquier D, Yazyev OV, Kis A. 2D transition metal dichalcogenides. Nat Rev Mater. 2017;2(8):17033. doi: 10.1038/natrevmats.2017.33.

122. McCallion C, Burthem J, Rees Unwin K, Golovanov A, Pluen A. Graphene in therapeutics delivery: problems solutions and future opportunities. Eur J Pharm Biopharm. 2016 Jul;104:235-50. doi: 10.1016/j.ejpb.2016.04.015, PMID 27113141.

123. Wu T, Jiang Q, Wu D, Hu Y, Chen S, Ding T. What is new in lysozyme research and its application in food industry? a review. Food Chem. 2019 Feb 15;274:698-709. doi: 10.1016/j.foodchem.2018.09.017, PMID 30372997.

124. Fu X, Lu Y, Guo J, Liu H, Deng A, Kuang C. K237-modified thermosensitive liposome enhanced the delivery efficiency and cytotoxicity of paclitaxel in vitro. J Liposome Res. 2019;29(1):86-93. doi: 10.1080/08982104.2018.1458863, PMID 29671386.

125. Monteiro LO, Lopes SC, Barros AL, Magalhaes Paniago R, Malachias A, Oliveira MC. Phase behavior of dioleyphosphatidylethanolamine molecules in the presence of components of pH-sensitive liposomes and paclitaxel. Colloids Surf B Biointerfaces. 2016 Aug 1;144:276-83. doi: 10.1016/j.colsurfb.2016.04.011, PMID 27100854.

126. Khosravi Z, Sharma S, Farnoud AM. Submicron polymeric particles accelerate insulin fibrillation by surface adsorption. Biointerphases. 2019;14(2):021001. doi: 10.1116/1.5083821, PMID 30841701.

127. Rocha S, Thunemann AF, Pereira Mdo C, Coelho M, Mohwald H, Brezesinski G. Influence of fluorinated and hydrogenated nanoparticles on the structure and fibrillogenesis of amyloid beta-peptide. Biophys Chem. 2008;137(1):35-42. doi: 10.1016/j.bpc.2008.06.010, PMID 18625543.

128. Linse S, Cabaleiro Lago C, Xue WF, Lynch I, Lindman S, Thulin E. Nucleation of protein fibrillation by nanoparticles. Proc Natl Acad Sci USA. 2007;104(21):8691-6. doi: 10.1073/pnas.0701250104, PMID 17485668.

129. Tian X, Chong Y, Ge C. Understanding the nano bio interactions and the corresponding biological responses. Front Chem. 2020 Jun 10;8:446. doi: 10.3389/fchem.2020.00446, PMID 32587847.

130. Griffin BT, Guo J, Presas E, Donovan MD, Alonso MJ, O Driscoll CM. Pharmacokinetic pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs. Adv Drug Deliv Rev. 2016;106(B):367-80. doi: 10.1016/j.addr.2016.06.006, PMID 27320644.

131. Ickrath P, Wagner M, Scherzad A, Gehrke T, Burghartz M, Hagen R. Time-dependent toxic and genotoxic effects of zinc oxide nanoparticles after long term and repetitive exposure to human mesenchymal stem cells. Int J Environ Res Public Health. 2017;14(12):1590. doi: 10.3390/ijerph14121590, PMID 29258234.

132. Di Cristo L, Maguire Cm, Mc Quillan K, Aleardi M, Volkov Y, Movia D. Towards the identification of an in vitro tool for assessing the biological behavior of aerosol supplied nanomaterials. Int J Environ Res Public Health. 2018 Mar 21;15(4):563. doi: 10.3390/ijerph15040563, PMID 29561767.

133. Roy S, Deo KA, Singh KA, Lee HP, Jaiswal A, Gaharwar AK. Nano-bio interactions of 2D molybdenum disulfide. Adv Drug Deliv Rev. 2022 Aug;187:114361. doi: 10.1016/j.addr.2022.114361, PMID 35636569.

134. Chaudhary K, Kumar K, Venkatesu P, Masram DT. In-depth understanding of a nano-bio interface between lysozyme and Au NP-immobilized N-doped reduced graphene oxide 2-D scaffolds. Nanoscale Adv. 2020;2(5):2146-59. doi: 10.1039/d0na00155d, PMID 36132509.

135. Tang Z, Xiao Y, Kong N, Liu C, Chen W, Huang X. Nano bio interfaces effect of two-dimensional nanomaterials and their applications in cancer immunotherapy. Acta Pharm Sin B. 2021;11(11):3447-64. doi: 10.1016/j.apsb.2021.05.004, PMID 34900529.

136. Ta T, Porter TM. Thermosensitive liposomes for localized delivery and triggered release of chemotherapy. J Control Release. 2013;169(1-2):112-25. doi: 10.1016/j.jconrel.2013.03.036, PMID 23583706.

137. Li F, Du Y, Liu J, Sun H, Wang J, Li R. Responsive assembly of upconversion nanoparticles for pH‐activated and near-infrared triggered photodynamic therapy of deep tumors. Adv Mater. 2018;30(35):e1802808. doi: 10.1002/adma.201802808, PMID 29999559.

138. Lee YJ, Lee JM, Lee JS, Lee HY, Park BH, Kim YH. Hepatocellular carcinoma: diagnostic performance of multidetector CT and MR imaging a systematic review and meta-analysis. Radiology. 2015;275(1):97-109. doi: 10.1148/radiol.14140690, PMID 25559230.

139. Frost B, Diamond Mi. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. 2010;11(3):155-9. doi: 10.1038/nrn2786, PMID 20029438.

140. Viles JH. Metal ions and amyloid fiber formation in neurodegenerative diseases copper zinc and iron in alzheimers parkinsons and prion diseases. Coord Chem Rev. 2012;256(19-20):2271-84. doi: 10.1016/j.ccr.2012.05.003.

141. Wu H, Li F, Wang S, Lu J, Li J, Du Y. Ceria nanocrystals decorated mesoporous silica nanoparticle-based ROS scavenging tissue adhesive for highly efficient regenerative wound healing. Biomaterials. 2018;151:66-77. doi: 10.1016/j.biomaterials.2017.10.018, PMID 29078200.

142. Glantz MJ, La Follette S, Jaeckle KA, Shapiro W, Swinnen L, Rozental JR. Randomized trial of a slow release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol. 1999;17(10):3110-6. doi: 10.1200/JCO.1999.17.10.3110, PMID 10506606.

143. Hong K, Drummond DC, Kirpotin D. Liposomes useful for drug delivery. United States Patent US 8 Hermes Biosciences Inc Inventor Assignee; 2012. p. 147.

144. Li Z, Zhang Y, Wurtz W, Lee JK, Malinin VS, Durwas Krishnan S. Characterization of nebulized liposomal amikacin (Arikace) as a function of droplet size. J Aerosol Med Pulm Drug Deliv. 2008;21(3):245-54. doi: 10.1089/jamp.2008.0686, PMID 18759656.

145. Yarosh DB, Kibitel JT, Green LA, Spinowitz A. Enhanced unscheduled DNA synthesis in UV-irradiated human skin explants treated with T4N5 liposomes. J Invest Dermatol. 1991;97(1):147-50. doi: 10.1111/1523-1747.ep12479314, PMID 2056185.

146. Petre CE, Dittmer DP. Liposomal daunorubicin as a treatment for kaposis sarcoma. Int J Nanomedicine. 2007;2(3):277-88. PMID 18019828.

147. Sarris AH, Hagemeister F, Romaguera J, Rodriguez MA, McLaughlin P, Tsimberidou AM. Liposomal vincristine in relapsed non-hodgkins lymphomas: early results of an ongoing phase II trial. Ann Oncol. 2000;11(1):69-72. doi: 10.1023/a:1008348010437, PMID 10690390.

148. Chang HI, Yeh MK. Clinical development of liposome-based drugs: formulation characterization and therapeutic efficacy. Int J Nanomedicine. 2012;7:49-60. doi: 10.2147/IJN.S26766, PMID 22275822.

149. Chen J, He CQ, Lin AH, Gu W, Chen ZP, Li W. Thermosensitive liposomes with higher phase transition temperature for targeted drug delivery to tumor. Int J Pharm. 2014;475(1-2):408-15. doi: 10.1016/j.ijpharm.2014.09.009, PMID 25218394.

150. Wang Y, Cai R, Chen C. The nano-bio interactions of nanomedicines: understanding the biochemical driving forces and redox reactions. Acc Chem Res. 2019;52(6):1507-18. doi: 10.1021/acs.accounts.9b00126, PMID 31149804.

151. Bhatt S, Punetha VD, Pathak R, Punetha M. Graphene in nanomedicine: a review on nano-bio factors and antibacterial activity. Colloids Surf B Biointerfaces. 2023 Jun;226:113323. doi: 10.1016/j.colsurfb.2023.113323, PMID 37116377.

152. Mahmoudi M, Landry MP, Moore A, Coreas R. The protein corona from nanomedicine to environmental science. Nat Rev Mater. 2023;8(7):422-38. doi: 10.1038/s41578-023-00552-2, PMID 37361608.

153. Saeed S, Ud Din SR, Khan SU, Gul R, Kiani FA, Wahab A. Nanoparticle: a promising player in nanomedicine and its theranostic applications for the treatment of cardiovascular diseases. Curr Probl Cardiol. 2023;48(5):101599. doi: 10.1016/j.cpcardiol.2023.101599, PMID 36681209.

154. Han X, Gong C, Yang Q, Zheng K, Wang Z, Zhang W. Biomimetic nano drug delivery system: an emerging platform for promoting tumor treatment. Int J Nanomedicine. 2024 Jan 18;19:571-608. doi: 10.2147/IJN.S442877, PMID 38260239.

155. Gong Z, Peng S, Cao J, Tan H, Zhao H, Bai J. Advances in the variations and biomedical applications of stimuli-responsive nano drug delivery systems. Nanotechnology. 2024 Jan 10;35(13). doi: 10.1088/1361-6528/ad170b, PMID 38198449.

156. Nanotechnology-based delivery systems to overcome drug resistance in cancer. Medical Review. 2024 Feb 20;4(1):5–30. doi: 10.1515/mr-2023-0058.

157. Moradi Kashkooli F, Hornsby TK, Kolios MC, Tavakkoli J. Ultrasound mediated nano-sized drug delivery systems for cancer treatment: multi-scale and multi-physics computational modeling. WIREs Nanomed Nanobiotechnol. 2024;16(1):e1913. doi: 10.1002/wnan.1913.

158. Hahn J, Ding S, IM J, Harimoto T, Leong KW, Danino T. Bacterial therapies at the interface of synthetic biology and nanomedicine. Nat Rev Bioeng. 2024;2(2):120-35. doi: 10.1038/s44222-023-00119-4, PMID 38962719.

159. Zhang P, Xiao Y, Sun X, Lin X, Koo S, Yaremenko AV. Cancer nanomedicine toward clinical translation: obstacles opportunities and future prospects. Med. 2023;4(3):147-67. doi: 10.1016/j.medj.2022.12.001, PMID 36549297.

160. Yellanki SK, Manoj AS, TM. Preparation and in vitro evaluation of metoprolol-loaded bovine serum albumin nanoparticles. Asian J Pharm Clin Res. 2021;14(1):213-7. doi: 10.22159/ajpcr.2021.v14i1.39738.

161. Sriramcharan P, Natarajan J, Raman R, Nagaraju G, Justin A, Senthil V. A review on green synthesis of cerium oxide nanoparticles: focus on central nervous system disorders. Int J App Pharm. 2022;14(4):94-102. doi: 10.22159/ijap.2022v14i4.44487.

162. Abdellatif MM, Ahmed SM, El-Nabarawi MA, Teaima M. Nano delivery systems for enhancing oral bioavailability of drugs. Int J App Pharm. 2023;15(1):13-9. doi: 10.22159/ijap.2023v15i1.46758.

163. Narayana S, Ahmed Mg, Nasrine A. Development of nano in situ gels of bevacizumab for the treatment of ocular angiogenesis: in vitro assessment of anti-angiogenesis activity and molecular docking analysis. Int J App Pharm. 2023;15(4):201-13. doi: 10.22159/ijap.2023v15i4.47860.

164. Zhang M, Lu H, Xie L, Liu X, Cun D, Yang M. Inhaled RNA drugs to treat lung diseases: disease-related cells and nano-bio interactions. Adv Drug Deliv Rev. 2023 Dec;203:115-44. doi: 10.1016/j.addr.2023.115144, PMID 37995899.

165. Saiding Q, Zhang Z, Chen S, Xiao F, Chen Y, Li Y. Nano-bio interactions in mRNA nanomedicine: challenges and opportunities for targeted mRNA delivery. Adv Drug Deliv Rev. 2023 Dec;203:115-6. doi: 10.1016/j.addr.2023.115116, PMID 37871748.

166. Liu J, Guo M, Chen C. Nano-bio interactions: a major principle in the dynamic biological processes of nano assemblies. Adv Drug Deliv Rev. 2022 Jul;186:114318. doi: 10.1016/j.addr.2022.114318, PMID 35533787.

167. Lin JH. Editor. Research article nano-bio interfacial interactions determined the contact toxicity of nTiO₂ to nematodes in various soils science of the total; 2022.

168. Ayushi Priyam. Multi-endpoint assessments for in vitro nano-bio interactions and uptake of biogenic phosphorus nanomaterials using HEK293 cells.
     Environ Sci: Adv. 2023:2:749-66. doi: 10.1039/D2VA00318J.

169. Shounak Roy, Kaivalya A Deo, Kanwar Abhay Singh. Nano-bio interactions of 2d molybdenum disulphide. Advanced Drug Delivery. 2022 Aug:187:114361. doi: 10.1016/j.addr.2022.114361.

170. Jagriti Gupta, Pradeep Kumar Vaid, Eepsita Priyadarshini, Paulraj Rajamani. Nano-bio convergence unveiled: systematic review on quantum dots protein interaction their implications and applications. Biophysical Chemistry. 2024 Jul;310:107238. doi: 10.1016/j.bpc.2024.107238.