Polymeric Nanogels Research Articles

Investigation of Dynamic Adsorption and Desorption of Polymer Nanogel in Porous Media through Microfluidics

Summary Understanding the transport and retention of elastic nanogel and microgel particles in porous media has been a significant research subject for decades, essential to the application of enhanced oil recovery (EOR). However, a lack of dynamic adsorption and desorption studies, in which the kinetics in porous media are seldom investigated, hinders the design and application of polymer nanogel in underground porous media. In this work, we visualized and quantified the transport and dynamic adsorption of polymer nanogel in 3D glass micromodels that were manufactured by packing glass beads in capillaries. Calibrating the linearity of fluorescence intensity to concentration, we calculated the adsorption kinetics at concentrations of 0.1 wt%, 0.2 wt%, and 0.3 wt% and flow rates of 0.01 mL/h, 0.02 mL/h, and 0.03 mL/h. In addition to time, concentration, and flow rate, the experimental results showed that dynamic adsorption is also a function of transport distance, which is due to the different adsorption abilities of particles. We also found that the uneven adsorption distribution can be attenuated by decreasing nanogel concentration or increasing flow rate. The work provides a new method to obtain adsorption and desorption kinetics and adsorption profile of submicron particles in porous media at flowing conditions through microfluidics.

Thermo sensitive and pH responsive surface modulated transdermal green tea nanogel: Structural, physiochemical and in vitro safety investigations

An altered simplistic biomimetic whole green tea extract-loaded nanogel (GE-C-NGL) was fabricated possessing pH-responsive and temperature-dependent intracellular transdermal nanotherapy. A biocompatible chitosan nanogel subsequently surface modified with oleic acid aiding Pluronic 127 discharging green tea extract on transdermal delivery was evaluated in light of structural, physiochemical, thermal, and in vitro toxicological factors by optical class, index class and spectrophotometrically class, and in vitro cell line toxicological evaluations, which precisely elaborated the nanosize particle size range and significant drug entrapment suggesting a spherical and thermo stable nanogel system. Additionally, sustained drug release configuration is displayed in mildly acidic conditions (pH 6) signifying ultra-pH sensitivity of GE-C-NGL. Moreover, strong mucin binding ability, pH-dependent swelling efficiency, negligible hemolytic ratio, and high antioxidant activity were obtained for enhanced transdermal efficacy. The comprehensive augmented polymeric blend transdermal nanogel, in light of the above preclinical biological and toxicological evaluations, evidently targets transdermal potential with promising bacterial biodegradable nanodrug therapy in clinical platforms.

Study on increasing polymer gel strength with Janus nanoparticles and its feasibility in profile control and water plugging

In formations subjected to prolonged flooding, dominant channels are formed in high permeability layers, thereby reducing the displacement efficiency in medium- and low-permeability layers. In this study, the Janus synthesis method was employed to produce Janus Nano-TiO2 with a particle size range of 60–120 nm and superior dispersion properties. These nanoparticles were subsequently combined with polyacrylamide to formulate a high-strength polymer nano-gel for water plugging applications. The successful synthesis of the material was confirmed through FTIR and TGA. Gelation experiments indicated that the gelation strength and time augmented significantly with the increased addition of Janus-T6. Conversely, an increase in temperature or salinity resulted in a reduction of both gelation strength and time. Rheological experiments demonstrated a decrease in polymer viscosity with rising shear rates or temperatures, revealing significant shear thinning behavior in the water-plugging agent solution. System viscosity increased with more Janus-T6. Flow experiments revealed decreasing resistance coefficients at higher permeabilities, while all cores exhibited plugging rates above 85%. Additionally, the breakthrough pressure continuously rose with the increased addition of Janus-T6. Ultimately, displacement experiments indicated a 22.83% increase in the recovery rate after employing PNG plugging followed by secondary water flooding, compared to primary water flooding alone.

Poly(N-isopropylacrylamide)-chitosan nanogels for nanotechnological and catalytic applications

Polymer nanogels consisting of poly(N-isopropylacrylamide) and chitosan [P(NC)] were synthesized using a free radical precipitation polymerization technique in an aqueous environment. This process involved the polymerization of N-isopropylacrylamide (NIPAAM) with chitosan (CS) and a cross-linker. These P(NC) nanogels were utilized as nano-reactors for the synthesis of gold nanoparticles (AuNPs), which were formed within the polymeric network through an in-situ reduction process using tetrachloroauric acid [H(AuCl4)] as precursor salt and sodium borohydride (NaBH4) as the reductant. Various analytical methods, including Transmission electron microscopy (TEM), Thermogravimetric analysis (TGA), Ultraviolet–visible spectroscopy (UV–Vis), and Fourier transform infrared spectroscopy (FTIR), were employed to confirm the formation of P(NC) nanogels and the incorporation and durability of AuNPs within the P(NC) nanogels. The AuNPs loaded P(NC) nanogels were utilized as catalysts for the reduction of 4-nitrophenol (4-NiP) into 4-aminophenol (4-AmP) in the presence of NaBH4. This system was also used to degrade a number of dyes including methylene blue (MB), methylene orange (MO), rhodamine B (RhB), brilliant blue (BB) and eosin Y ((EY) by using NaBH4 as a reducing agent. The Au-P(NC) catalyst exhibited remarkable efficiency, facilitating the fast reduction of 4-NiP and degradation of dyes within a very short interval of time. This system stands out for its economic usage, as even a small quantity of it can efficiently reduce toxic pollutants like 4-NiP and dyes. The results of the reactions highlighted exceptional yield, emphasizing the effectiveness and recyclability of the Au-P(NC) hybrid nanogels as highly capable catalysts.

Hyaluronic Acid in Nanopharmaceuticals: An Overview.

Hyaluronic acid (HA) is a naturally occurring, long, unbranched polysaccharide that plays a critical role in maintaining skin structure and hydration. Its unique properties make it a valuable component in the field of nanopharmaceuticals. The combination of HA into nanopharmaceuticals enhances its ability to interact with various therapeutic agents, improving the delivery and efficacy of drugs. HA-based nanoparticles, including solid lipid nanoparticles, and polymeric nanogels, offer controlled release, enhanced stability, and targeted delivery of therapeutic agents. These innovations significantly improve therapeutic outcomes and reduce side effects, making HA an essential tool in modern medicine. In general, HA-modified liposomes enhance drug encapsulation and targeting, while HA-modified solid lipid nanoparticles (SLNs) provide a solid lipid core for drug encapsulation, offering controlled release and stability. This article provides an overview of the potential applications and recent advancements of HA in nanopharmaceuticals, emphasizing its significant impact on the evolving field of targeted drug delivery and advanced therapeutic strategies. By delving into the unique properties of HA and its compatibility with various therapeutic agents, this review underscores the promising potential of HA in revolutionizing nanopharmaceuticals.

Multifunctional Silver‐Enzyme Nanogels Assembly with Efficient Trienzyme Cascades for Synergistic Diabetic Wound Healing

AbstractDiabetic wound healing presents a persistent clinical challenge, often characterized by prolonged healing times, and can be particularly difficult to achieve in a hyperglycemic environment. In this study, a multi‐functional silver‐enzyme nanogels assembly (Ag‐nGHC) is designed by focusing on the complex diabetic wound environment. Glucose oxidase (GOX), horseradish peroxidase (HRP), and catalase (CAT) are modified within polymeric nanogel layers and assembled into a large enzyme cluster with silver ions. The close attachment of three enzymes ensures fast and continuous consumption of a high level of glucose, generation of oxygen, and hydroxyl radicals (•OH) around the wound site. Meanwhile, the silver ions within the Ag‐nGHC assembly act as an effective agent to kill bacteria. This cascade enzyme system significantly improves the microenvironment of the wound site by reducing bacterium infection and alleviating hypoxia as well as hyperglycemia. Sequentially, the improved environment facilitates the later processes including anti‐inflammatory, re‐epithelialization, and angiogenesis, evidenced by enhancing polarization toward M2 macrophages and increasing CD31 signals in this study. Overall, the Ag‐nGHC materials are proven to achieve multifunctional properties toward complicated diabetic wound healing processes (attributes such as adaptability, hypoxia‐alleviated, anti‐hyperglycemic, antimicrobial, anti‐inflammatory, and angiogenic) and showed great potential for the treatment of chronic diabetic wound.

Modulating the Mucosal Drug Delivery Efficiency of Polymeric Nanogels Tuning their Redox Response and Surface Charge

AbstractMucus is a hydrated, viscoelastic, and adhesive gel that lubricates and protects the body from pathogens; however, its protective function hinders drug/nanomedicine diffusion and treatment efficiency. Therefore, novel drug delivery strategies are required to overcome challenging mucosal barriers. Here, multi‐responsive nanogels (NGs) are developed and explored their interaction with mucus. Specific NG features (e.g., surface charge, temperature responsiveness, and redox response) are evaluated in a typical mucus‐associated environment (i.e., mucin proteins and high glutathione concentrations). The results demonstrate that biocompatibility and the capacity to deliver a protein through mucosal barriers in different in vitro and in vivo models highlight the importance of specific NG design elements. Disulfide bonds are highlighted as redox‐sensitive cross‐linkers within the NG structure as critical for drug delivery performance; they function as degradation points that enable NG degradation and subsequent drug release and anchoring points to adhere to mucin, thereby enhancing their residence time at the desired site of action. Additionally, it is confirmed that surface charges impact interactions with mucin; positively charged NGs exhibit improved interactions with mucin compared to negatively charged and neutral NGs. Overall, the findings underline the importance of redox response and surface charge in NG design for reaching efficient mucosal drug delivery.

Poly(vinyl alcohol)-Incorporated Core-Shell Polymer Nanogels Functionalized by Block Copolymer Installation for Cisplatin Delivery.

The functionalization approach for nanomaterials is of great importance for their application in drug delivery systems. Herein, an approach based on block copolymer installation into polymer nanogels was newly developed. Poly(vinyl alcohol)-incorporated polymer nanogels were prepared by a two-step dispersion/precipitation polymerization. Poly(methacrylic acid)-block-poly(3-fluorophenylboronic acid methacrylamide) (PMAA-b-PFPBMA) prepared by two-step reversible addition-fragmentation chain transfer polymerization was installed into the polymer nanogels via boronate ester formation. Furthermore, cisplatin as a cancer therapeutic drug was successfully loaded on the block copolymer-installed polymer nanogels, and cell death was achieved by using the resulting cisplatin-loaded nanogels. We believe that the functionality of the nanogels can be changed by varying the installed block copolymer, leading to the functionalization approach of polymer nanogels based on block copolymer installation, which will be of great utility in many fields.

Self-Reporting Therapeutic Protein Nanoparticles.

We present a modular strategy to synthesize nanoparticle sensors equipped with dithiomaleimide-based, fluorescent molecular reporters capable of discerning minute changes in interparticle chemical environments based on fluorescence lifetime analysis. Three types of nanoparticles were synthesized with the aid of tailor-made molecular reporters, and it was found that protein nanoparticles exhibited greater sensitivity to changes in the core environment than polymer nanogels and block copolymer micelles. Encapsulation of the hydrophobic small-molecule drug paclitaxel (PTX) in self-reporting protein nanoparticles induced characteristic changes in fluorescence lifetime profiles, detected via time-resolved fluorescence spectroscopy. Depending on the mode of drug encapsulation, self-reporting protein nanoparticles revealed pronounced differences in their fluorescence lifetime signatures, which correlated with burst- vs diffusion-controlled release profiles observed in previous reports. Self-reporting nanoparticles, such as the ones developed here, will be critical for unraveling nanoparticle stability and nanoparticle-drug interactions, informing the future development of rationally engineered nanoparticle-based drug carriers.

Rational Design of Highly Selective Sialyllactose-Imprinted Nanogels.

We describe a facile method to prepare water-compatible molecularly imprinted polymer nanogels (MIP NGs) as synthetic antibodies against target glycans. Three different phenylboronic acid (PBA) derivatives were explored as monomers for the synthesis of MIP NGs targeting either α2,6- or α2,3-sialyllactose, taken as oversimplified models of cancer-related sT and sTn antigens. Starting from commercially available 3-acrylamidophenylboronic acid, also its 2-substituted isomer and the 5-acrylamido-2-hydroxymethyl cyclic PBA monoester derivative were initially evaluated by NMR studies. Then, a small library of MIP NGs imprinted with the α2,6-linked template was synthesized and tested by mobility shift Affinity Capillary Electrophoresis (msACE), to rapidly assess an affinity ranking. Finally, the best monomer 2-acrylamido PBA was selected for the synthesis of polymers targeting both sialyllactoses. The resulting MIP NGs display an affinity constant≈106 M-1 and selectivity towards imprinted glycans. This general procedure could be applied to any non-modified carbohydrate template possessing a reducing end.

Facile biotic/abiotic sandwich detection system for the highly sensitive detection of human serum albumin and glycated albumin

Quantifying glycated albumin (GA) levels in the blood is crucial for diagnosing diabetes because they strongly correlate with blood glucose concentration. In this study, a biotic/abiotic sandwich assay was developed for the facile, rapid, and susceptible detection of human serum albumin (HSA) and GA. The proposed sandwich detection system was assembled using a combination of two synthetic polymer receptors and natural antibodies. Molecularly imprinted polymer nanogels (MIP-NGs) for HSA (HSA-MIP-NGs) were used to mimic capture antibodies, whereas antibodies for HSA or GA were used as primary antibodies and fluorescent signaling MIP-NGs for the Fc domain of IgG (F-Fc-MIP-NGs) were used as a secondary antibody mimic to indicate the binding events. The HSA/anti-HSA/F-Fc-MIP-NGs complex, formed by incubating HSA and anti-HSA antibodies with F-Fc-MIP-NGs, was captured by HSA-MIP-NGs immobilized on the chips for fluorescence measurements. The analysis time was less than 30 min, and the limit of detection was 15 pM. After changing the anti-HSA to anti-GA (monoclonal antibody), the fluorescence response toward GA exceeded that of HSA, indicating successful GA detection using the proposed sandwich detection system. Therefore, the proposed system could change the detection property by changing a primary antibody, indicating that this system can be applied to various target proteins and, especially, be a powerful approach for facile and rapid analysis methods for proteins with structural similarity.Graphical

Construction of biomimetic camouflaged neutrophil membrane nanoparticles for precise delivery and augmented glioma cancer treatment

Developing novel nanomedicine formulations that successfully penetrate the blood-brain barrier (BBB) to treat and diagnose glioma effectively is still a significant obstacle. This study presents the development of polymer nanogels camouflaged with macrophage membranes. The nanogels are loaded with manganese dioxide (MnO2) and carboplatin. They are designed for the treatment of glioma using a combination of chemotherapy and chemodynamic therapy (CDT). The precipitation polymerization process was used to create redox-responsive poly(caprolactone) (PCL) nanogels (NGs). These NGs were then loaded with MnO2 and physically encapsulated with carboplatin. The resulting nanogels had an average diameter of 102.52 nm and were covered with macrophage membranes to provide excellent stability. The developed NGs exhibit redox and pH responsiveness, releasing carboplatin and Mn(II) in a controlled manner. NGs may effectively deplete glutathione (GSH) in the tumour milieu. The Mn(II) generated in this process enhances the effectiveness of the loaded carboplatin by exerting its chemotherapeutic action and promoting the formation of reactive oxygen species to improve the efficiency of CDT. The results of our study show a very efficient and promising nanomedicine platform for the treatment and diagnosis of glioma, a type of cancer. This platform is self-adaptive, cooperative, and based on NG technology. Furthermore, this platform can potentially be used for other challenging types of cancer.

Formulation and In Vitro Assessment of Polymeric pH-Responsive Nanogels of Chitosan for Sustained Delivery of Madecassoside.

Madecassoside, a triterpenoid saponin compound mainly isolated from the gotu kola herb (Centella asiatica), shows an extensive range of biological activities, including antiapoptotic, antioxidant, anti-inflammatory, moisturizing, neuroprotective, and wound healing effects. It has been highly used in the management of eczema, skin wounds, and other diseases. Due to poor oral bioavailability, membrane permeability, and intestinal absorption, the clinical application of the madecassoside is limited. Hence, a drug carrier system is needed that not only sustains the release of the madecassoside but also overcomes the drawbacks associated with its administration. Therefore, the authors prepared novel pH-responsive chitosan-based nanogels for the sustained release of madecassoside. Free radical polymerization technique was used for cross-linking of polymer chitosan and monomer methacrylic acid in the presence of cross-linker N',N'-methylene bis(acrylamide). The decrease in polymer crystallinity after polymerization and development of nanogels was demonstrated by XRD and FTIR analysis. The effects of nanogel contents on polymer volume, sol-gel analysis, swelling, drug loading, and release were investigated. Results indicated that high swelling and maximum release of the drug occurred at pH 7.4 compared to pH 1.2 and 4.6, indicating the excellent pH-sensitive nature of the engineered nanogels. High swelling and drug release were perceived with the integration of a high quantity of chitosan, while a decline was observed with the high integration of N',N'-methylene bis(acrylamide) and methacrylic acid contents. The same effects of nanogel contents were shown for drug loading too. Sol fraction was reduced, while gel fraction was enhanced by increasing the chitosan load, N',N'-methylene bis(acrylamide), and methacrylic acid. The Korsmeyer-Peppas model of kinetics was trailed by all nanogel formulations with non-Fickian diffusion. The results demonstrated that prepared nanogels can be employed for sustained release of the madecassoside.

Hydrogen-bonded cytosine-endowed supramolecular polymeric nanogels: Highly efficient cancer cell targeting and enhanced therapeutic efficacy

We demonstrate that cytosine moieties within physically cross-linked supramolecular polymers not only manipulate drug delivery and release, but also confer specific targeting of cancer cells to effectively enhance the safety and efficacy of chemotherapy—and thus hold significant potential as a new perspective for development of drug delivery systems. Herein, we successfully developed physically cross-linked supramolecular polymers (PECH-PEG-Cy) comprised of hydrogen-bonding cytosine pendant groups, hydrophilic poly(ethylene glycol) side chains, and a hydrophobic poly(epichlorohydrin) main chain. The polymers spontaneously self-assemble into a reversibly hydrogen-bonded network structure induced by cytosine and directly form spherical nanogels in aqueous solution. Nanogels with a high hydrogen-bond network density (i.e., a higher content of cytosine moieties) exhibit outstanding long-term structural stability in cell culture substrates containing serum, whereas nanogels with a relatively low hydrogen-bond network density cannot preserve their structural integrity. The nanogels also exhibit numerous unique physicochemical characteristics in aqueous solution, such as a desirable spherical size, high biocompatibility with normal and cancer cells, excellent drug encapsulation capacity, and controlled pH-responsive drug release properties. More importantly, in vitro experiments conclusively indicate the drug-loaded PECH-PEG-Cy nanogels can selectively induce cancer cell-specific apoptosis and cell death via cytosine receptor-mediated endocytosis, without significantly harming normal cells. In contrast, control drug-loaded PECH-PEG nanogels, which lack cytosine moieties in their structure, can only induce cell death in cancer cells through non-specific pathways, which significantly inhibits the induction of apoptosis. This work clearly demonstrates that the cytosine moieties in PECH-PEG-Cy nanogels confer selective affinity for the surface of cancer cells, which enhances their targeted cellular uptake, cytotoxicity, and subsequent induction of programmed cell death in cancer cells.

Fabrication and evaluation of cross-linked nanogels of Dexibuprofen

The objective of this study was to design and develop an Agarose-based polymeric nanogel network system for solubility enhancement of a lipophilic drug, Dexibuprofen. Polymeric nanogels were synthesized through free radical polymerization where Agarose was cross-linked with 2-Acrylamido-2-methylpropane sulfonic acid (AMPS) in the presence of ammonium persulfate (APS) as an initiator and N, N’-Methylenebisacrylamide (MBA) as crosslinking agent. The resulting polymeric nanogels underwent a comprehensive characterization process including Fourier transform infrared (FTIR), particle size analysis, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), powder X-ray diffraction (PXRD), and swelling studies to confirm the preparation of a stable polymeric nanogel system. FTIR spectral findings revealed that Agarose was chemically cross-linked with AMPS and confirmed the successful insertion of AMPS chains on the Agarose backbone. Particle size analysis revealed a diameter of 168 nm with a zeta potential of −9.91 mV, providing assurance of a stable polymeric nanogel system. SEM images depicted a highly porous surface. DSC and TGA results showed a more thermally stable network system than individual ingredients. Swelling studies revealed an increased swelling ratio of polymeric nanogels at phosphate buffer of pH 6.8 than acidic buffer of pH 1.2. Dexibuprofen was efficiently loaded into a polymeric nanogel system with a high entrapment efficiency of up to 80%. The solubility of the drug was enhanced when introduced to a polymeric nanogel formulation when compared to pure drug. The system reproducibility was evaluated through in vitro drug release and kinetic modeling of drug release. Toxicity studies confirmed the formulation’s effectiveness, showcasing the developed polymeric nanogels as a promising option for delivering lipophilic drugs, with outstanding physicochemical properties, improved solubility, and minimal oral toxicity.

One-Dimensional Responsive Photonic Crystals Assembled by Polymer Nanogels and TiO2 Nanoparticles for Rapid Detection of Glucose

One-Dimensional Responsive Photonic Crystals Assembled by Polymer Nanogels and TiO₂ Nanoparticles for Rapid Detection of Glucose

Enzyme stability in polymer hydrogel-enzyme hybrid nanocarrier containing phosphorylcholine group.

Enzymes are biological catalysts with good biocompatibility and high efficiency and have been widely used in many fields, such as wastewater treatment, biosensors, and the medical industry. However, their inherently low stability under conditions of practical use limits further applications. Zwitterionic polymers possessing a pair of oppositely charged groups in their repeating units can increase protein stability because of their good biocompatibility and high water content. In this study, zwitterionic copolymer nanogels comprising poly(2-methacryloyloxyethyl phosphorylcholine (MPC)-co-methacrylic acid-N-hydroxy succinimide ester (MNHS)) (PMS) were synthesized via reversible addition-fragmentation chain-transfer polymerization (RAFT). β-Galactosidase (β-gal) was post-modified within zwitterionic polymer nanogels with a covalently-bound spacer and the activity was compared with that of directly immobilized β-gal and free β-gal. Compared with direct immobilization, covalent immobilization with a spacer could reduce the structural change of β-gal, as confirmed by the circular dichroism spectra. Although the activity of β-gal decreased after immobilization, the hybrids of the β-gal immobilized nanogels, termed hybrid nanogel-enzymes, demonstrated superior stability compared to the free enzymes. The hybrid nanogel-enzymes maintained their function against inactivation by organic solvents and proteinases owing to their high water content, anti-biofouling properties, and limited mass transfer. They can also withstand protein aggregation at high temperatures and maintain their activity. Compared to direct immobilization, immobilization with a spacer resulted in a dramatic increase in the enzyme activity and a slight decrease in the stability. These results indicate that polymer nanogels containing phosphorylcholine units are promising materials for enzyme immobilization, expanding the scope of enzyme applications.

One-step flow synthesis of size-controlled polymer nanogels in a fluorocarbon microfluidic chip.

Synthetic polymer nanoparticles (NPs) with biomimetic properties are ideally suited for different biomedical applications such as drug delivery and direct therapy. However, bulk synthetic approaches can suffer from poor reproducibility and scalability when precise size control or multi-step procedures are required. Herein, we report an integrated microfluidic chip for the synthesis of polymer NPs. The chip could sequentially perform homopolymer synthesis and subsequent crosslinking into NPs without intermediate purification. This was made possible by fabrication of the chip with a fluorinated elastomer and incorporation of two microfluidic mixers. The first was a long channel with passive mixing features for the aqueous RAFT synthesis of stimuli-responsive polymers in ambient conditions. The polymers were then directly fed into a hydrodynamic flow focusing (HFF) junction that rapidly mixed them with a crosslinker solution to produce NPs. Compared to microfluidic systems made of PDMS or glass, our chip had better compatibility and facile fabrication. The polymers were synthesized with high monomer conversion and the NP size was found to be influenced by the flow rate ratio between the crosslinker solution and polymer solution. This allowed for the size to be predictably controlled by careful adjustment of the fluid flow rates. The size of the NPs and their stimuli-responses were studied using DLS and SEM imaging. This microfluidic chip design can potentially streamline and provide some automation for the bottom-up synthesis of polymer NPs while offering on-demand size control.

Post-polymerization functionalized sulfonium nanogels for gene delivery

Cross-linked polymer nanogels with positively charged sulfonium groups were designed and synthesized. After characterization, the gene delivery propensity of these materials was evaluated, which is likely hampered by limited cell entry.

Investigating the Impact of Network Functionalization on Protein Adsorption to Polymer Nanogels.

This study explores the impact of network functionalization and chemical composition on the pH-responsive behavior of polymer nanogels and their adsorption of proteins. Using a thermodynamic theory informed by a molecular model, this work evaluates the interactions of three proteins with varying isoelectric points (insulin, myoglobin, and cytochrome c) and pH-responsive nanogels based on methacrylic acid or allylamine motifs. Three different functionalization strategies are considered, with pH-responsive segments distributed randomly, at the center, or on the surface of the polymer network. Our results show that the spatial distribution of functional units affects both the nanogels' mechanical response to pH changes and the level and localization of adsorbed proteins. The dependence of protein adsorption on the salt concentration is also investigated, with the conclusion that it is best to encapsulate proteins at low salt concentrations and aim for release at high salt concentrations. These results provide valuable information for the design of pH-responsive nanogels as vehicles for protein encapsulation, transport, and administration.