Charge-switching nanogels represent an advanced class of polymeric nanomaterials engineered for targeted drug delivery across mucosal barriers, including oral and nasal routes. These systems leverage pH-responsive properties to dynamically alter surface charge, enabling precise control over mucoadhesion and mucopenetration. The ability to switch between cationic and anionic states in response to physiological pH gradients enhances drug bioavailability while minimizing off-target effects.

The foundation of charge-switching nanogels lies in their tunable polymer chemistry. Typically, these nanogels incorporate ionizable functional groups such as carboxylate (-COOH) or amine (-NH2) moieties within their crosslinked networks. At acidic pH, prevalent in the stomach or nasal mucosa, carboxylate groups protonate, reducing negative charge density, while amine groups gain protons, becoming positively charged. This shift to a cationic state promotes electrostatic interactions with the anionic mucin glycoproteins, enhancing mucoadhesion. Conversely, at neutral or slightly alkaline pH, such as in intestinal or systemic environments, the carboxylate groups deprotonate, while amines lose protons, rendering the nanogel surface anionic. This transition reduces mucoadhesion and facilitates mucopenetration, enabling deeper tissue permeation for systemic drug uptake.

Mucoadhesion is governed by multiple mechanisms beyond electrostatic interactions. Hydrogen bonding, hydrophobic effects, and physical entanglement with mucin fibers contribute to retention at mucosal surfaces. Charge-switching nanogels optimize these interactions by balancing adhesive and penetrative properties. For instance, a nanogel with high cationic charge density at pH 5.0 may exhibit strong mucoadhesion in the nasal cavity, while its anionic state at pH 7.4 promotes diffusion across the epithelial barrier. The nanogel’s mesh size, swelling ratio, and crosslinking density further influence drug release kinetics and mucosal interaction dynamics.

A critical application of charge-switching nanogels is oral insulin delivery. Insulin, a peptide therapeutic, faces enzymatic degradation and poor absorption in the gastrointestinal tract. Nanogels loaded with insulin can exploit the stomach’s acidic pH to adhere to the gastric mucosa, protecting the payload from proteolysis. Upon transit to the small intestine, the pH-triggered charge reversal minimizes mucoadhesion, allowing the nanogels to penetrate the mucus layer and release insulin near the absorptive epithelium. Studies demonstrate that such systems achieve significant hypoglycemic effects in diabetic models, with blood glucose reduction exceeding 50% within 4 hours post-administration. The insulin encapsulation efficiency in these nanogels often exceeds 80%, with sustained release profiles spanning 12 to 24 hours.

Nasal delivery represents another promising avenue, leveraging the nasal mucosa’s high vascularity and avoidance of first-pass metabolism. Charge-switching nanogels designed for intranasal administration adhere to the mucosal surface at pH 5.5–6.5, common in nasal secretions, then release drugs upon charge reversal triggered by physiological pH or enzymatic cues. For example, nanogels delivering antimigraine drugs exhibit rapid absorption, with plasma concentrations peaking within 30 minutes, comparable to intravenous injection. The mucopenetration phase is critical here, as excessive adhesion can hinder drug absorption, while insufficient retention leads to premature clearance.

Comparative studies highlight the advantages of charge-switching nanogels over conventional mucoadhesive systems. Non-switching cationic nanogels often suffer from prolonged mucosal retention, leading to irritation or incomplete drug release. Conversely, anionic or neutral nanogels may fail to adhere adequately, reducing residence time. Charge-switching systems address these limitations by adapting to microenvironmental changes. For instance, a nanogel transitioning from +15 mV at pH 5.0 to -20 mV at pH 7.4 demonstrates optimal mucoadhesion-penetration balance, whereas static cationic systems maintain +25 mV regardless of pH, resulting in suboptimal performance.

Material selection is pivotal in designing charge-switching nanogels. Common polymers include poly(acrylic acid) (PAA), chitosan, and their derivatives, often copolymerized with polyethylene glycol (PEG) to enhance biocompatibility. Chitosan-based nanogels exploit the polymer’s innate mucoadhesion and biodegradability, while PAA contributes pH-responsive charge modulation. PEGylation reduces opsonization, prolonging circulation time post-mucosal penetration. The nanogel synthesis typically involves emulsion polymerization or inverse nanoprecipitation, yielding particles sized 50–200 nm, ideal for mucosal transport.

Challenges remain in scaling up production and ensuring batch-to-batch consistency. Variations in crosslinking density or functional group distribution can alter charge-switching behavior and drug release profiles. Sterilization methods, such as gamma irradiation or filtration, must preserve nanogel integrity, as heat-based techniques may degrade sensitive polymers. Regulatory considerations also demand rigorous characterization of swelling kinetics, charge reversal thresholds, and long-term stability under physiological conditions.

Future directions include multifunctional nanogels integrating stimuli beyond pH, such as enzyme-responsive or redox-sensitive elements. Dual-responsive systems could further refine spatiotemporal drug release, particularly for biologics like vaccines or monoclonal antibodies. Advances in computational modeling aid in predicting charge-switching behavior, optimizing polymer compositions before synthesis.

In summary, charge-switching nanogels offer a versatile platform for mucosal drug delivery, harmonizing mucoadhesion and penetration through pH-triggered charge reversal. Their success in oral and nasal delivery, exemplified by insulin and antimigraine applications, underscores their potential to overcome longstanding bioavailability challenges. Continued innovation in polymer chemistry and fabrication techniques will expand their therapeutic scope while addressing translational hurdles.