Microenvironment-responsive size-adaptive nanoparticles: hyaluronidase/acid/NIR light activation for deep-penetration trimodal therapy

The dense tumor microenvironment (TME) hinders drug delivery. Herein, we report hyaluronidase (HAase)/acid/near-infrared (NIR) light-responsive, size-adaptive nanoparticles (NPs) co-loaded with doxorubicin (DOX) and IR780 (IDHNs). IDHNs integrate dual targeting with size-fissile capability: biocompatible human serum albumin (HSA) prolongs circulation; while hyaluronic acid (HA) enables CD44-mediated accumulation and HAase-triggered fission reduces particle size, facilitating deep stromal penetration. Acidic TME and NIR laser irradiation further accelerates drug release, achieving potent chemo-photothermal/photodynamic synergy. In vitro and in vivo studies confirm that IDHNs surpass monotherapies in precision, efficacy, and safety. This trimodal nanoplatform provides a versatile strategy to overcome physical TME barriers and advance tumor-targeted therapy.