Near-infrared light-activated smart nanogels for remotely controlled cytochrome c release and photodynamic therapy

[Display omitted] •The NASNs were fabricated by chemical cross-linking between polymer ligand and containing TK crosslinkers.•Obtained NASNs exhibited excellent stability and high protein loading capacity.•The NASNs can enhance cellular uptake and endo-lysosomal escape.•CC release can be promoted by NIR light-triggered 1O2 release.•The NASNs showed good cancer cell killing efficiency and biocompatibility.•The NASNs had potential utilities for remote and on-demand CC delivery and combined PDT. The utilization of reactive oxygen species (ROS) generated through photodynamic therapy (PDT) for remote-controlled release of protein drugs at specific sites using near-infrared light represents a groundbreaking development in protein delivery system innovation. To illustrate this principle, we engineered near-infrared light-activated smart nanogels (NASNs) by chemically cross-linking ROS-responsive linkages within hyaluronic acid-graft-methoxy poly(ethylene glycol)-diethylenetriamine-grafted-chlorine e6 (Ce6) polymer (HA-PEG-Dien-g-Ce6) and carboxylated thioketal (TK) serving as a cross-linker to enable PDT-driven cytochrome c (CC) liberation. The NASNs demonstrated substantial loading capacity and exceptional stability across diverse biological settings, attributed to the robust nature of the TK bond. Notably, CC-loaded NASNs effectively penetrated A549 cells via CD44-mediated endocytosis and rapidly escaped from the endo-lysosomal compartment. Upon light activation, the Ce6 produced ROS, leading to TK bond disruption in NASNs, and consequent release of encapsulated CC. This precise, photo-induced PDT mechanism and CC liberation markedly enhanced antitumor efficacy while maintaining minimal toxicity, establishing a solid foundation for remote, as-needed protein delivery systems and potential integration with additional therapeutic modalities.