Stimuli-responsive hydrogels in targeted cancer therapy: A systematic review of materials, mechanisms, and delivery strategies
Aynur S. Yilmaz, Alfonso Pepe, Neda Latifi, W. Gregory Sawyer, Michael Dunne
Abstract
Hydrogels are versatile platforms for targeted and controlled anticancer agent delivery, offering unique advantages like tunable degradation and responsiveness to tumor microenvironmental cues. This review presents a comprehensive design framework and classification for stimuli-responsive hydrogels based on five core criteria: material composition, polymerization technique, crosslinking chemistry, degradation mechanism, and therapeutic delivery profile. Natural polymers (e.g., chitosan, alginate, hyaluronic acid) are evaluated alongside synthetic matrices (e.g., polyethylene glycol, polyacrylamide, methacrylates), emphasizing their structure–function relationships and synthesis methods. Special attention is given to crosslinking strategies that incorporate tumor microenvironment-cleavable bonds and dynamic linkages. These designs precisely tune network architecture, mechanical stability, and degradation kinetics to match tumor-associated acidic, enzymatic, or redox conditions, achieving spatially and temporally controlled drug release. The review examines degradation mechanisms triggered by pH, redox, enzymes, heat, and external stimuli (light or ultrasound). We also discuss hybrid systems that integrate nanoparticles or genetic cargos (e.g., DNA, siRNA, antibodies) to enhance precision and multifunctionality. Quantitative analysis of literature trends is provided through visual maps. By linking molecular crosslinking design to therapeutic performance, this work offers a key reference for rationally developing next-generation smart hydrogels for translational cancer therapy.