Injectable smart hydrogel with dual pH/thermal responsiveness: A PCL–PEG–PCL/niosome synergistic platform for precision drug delivery

Achieving site-specific, on-demand drug release in response to physiological stimuli remains a critical hurdle in precision medicine. In this study, we introduce a smart, injectable nanocomposite hydrogel that combines thermoresponsive behavior with a degradation-triggered pH-responsive mechanism to enable precise and controlled therapeutic delivery. This platform is based on poly(ε-caprolactone)-b-poly(ethyleneglycol)-b-poly(ε-caprolactone) (PCEC) hydrogel matrix, co-loaded with dexamethasone (DEX) and ZnO nanoparticles encapsulated in niosomes (N/DEX/ZnO). The PCEC hydrogel, synthesized through ring-opening polymerization, exhibited thermoresponsive in situ gelation at physiological temperature, enabling formation of a stable depot at the injection site. Critically, the slow degradation of the hydrophobic, semicrystalline PCEC matrix (∼37 % over one month) produced a localized drop in pH (from 7.4 to ∼5.5), shifting the microenvironment from neutral (pH 7.4) to acidic (approximately pH 5.5). This localized acidification triggered ZnO nanoparticle dissolution, which in turn enabled a controlled, pH-sensitive release of drug from the niosomal carriers. In vitro release studies demonstrated a significantly enhanced cumulative release of DEX under acidic conditions, characterized by a biphasic release profile. Cell viability assays using human foreskin fibroblast (HFF) cells confirmed excellent cytocompatibility, with cell viability exceeding 85 % after 24 h of exposure. Additionally, in vivo subcutaneous administration of both PCEC and N/DEX/ZnO@PCEC hydrogels resulted in robust gel formation and favorable histopathological outcomes, with no significant inflammatory responses detected. Collectively, these findings highlight this smart, injectable hydrogel platform as a promising candidate for localized, sustained, and feedback-responsive drug delivery in therapeutic applications.