Mucoadhesive TannicAcid-Cross-Linked Nanogels forReactive Oxygen Species Scavenging and Enhanced Ocular TherapeuticDelivery

Mucoadhesive nanoparticles show promise for mucosal drug delivery, but ocular applications remain limited by rapid clearance, poor retention, and insufficient drug encapsulation. Existing systems struggle to deliver a full spectrum of therapeutics, hydrophobic drugs, hydrophilic drugs, and proteins, despite the critical need for such versatility in treating complex ocular diseases. Many eye conditions, including infection, inflammation, and degenerative disorder, require combination therapies or multidrug regimens for optimal therapeutic outcomes. To address these limitations, we developed a biocompatible tannic acid (TA)-cross-linked nanogel (NG) platform with robust mucoadhesion, anti-inflammatory, reactive oxygen species (ROS) scavenging properties, and sustained drug-release capabilities. The NGs were synthesized from a temperature-responsive poly(ethylene glycol)-based copolymer that self-aggregates above its lower critical solution temperature and is cross-linked with TA. TA’s polyphenolic structure enables multimodal mucoadhesion and antioxidant activity, enhancing ocular retention and protecting against ROS-induced damage. The NGs achieved high loading efficiency (>80%) for diverse therapeutics, including moxifloxacin, a hydrophilic antibiotic; dexamethasone (Dex), a hydrophobic anti-inflammatory drug; as well as bovine serum albumin, used as a model protein to explore potential for protein encapsulation. In proof-of-concept studies, Dex-loaded NGs demonstrated sustained release (>24 days) and therapeutic efficacy <i>in vitro</i> and <i>in vivo</i>. Blank NGs also exhibited anti-inflammatory activity <i>in vivo</i>, comparable to Dex-loaded NGs in an acute model of ocular inflammation, demonstrating their intrinsic therapeutic potential. By enabling delivery of multiple therapeutic classes while providing inherent anti-inflammatory function, this TA-cross-linked NG platform offers a versatile and effective strategy for managing complex ocular diseases.