Engineered Cell‐Derived Nanovesicles with CAR and PH20 for Enhanced Targeted Photodynamic Cancer Therapy and Tumor Microenvironment Modulation

Abstract Photodynamic therapy (PDT) is a promising cancer treatment, but its clinical use is limited by nontargeted photosensitizers (PS) that accumulate in normal tissues, causing adverse effects, and poor penetration in tumor tissues due to the dense extracellular matrix (ECM). Here an innovative approach is presented using cell‐derived nanovesicles (CNVs) engineered with chimeric antigen receptor (CAR) and hyaluronidase PH20 to enhance targeted PDT. The CAR–PH20 CNVs, loaded with the photosensitizer pheophorbide a (PheoA), specifically target HER2‐expressing tumor cells and degrade hyaluronic acid in the tumor microenvironment (TME), improving tumor penetration and drug distribution. In vitro and in vivo experiments demonstrate increased reactive oxygen species (ROS) generation, improved tumor retention, and enhanced therapeutic efficacy compared to conventional methods. When combined with laser irradiation, these CNVs induce significant tumor cell apoptosis and inhibit tumor growth in mouse models, while minimizing toxicity to normal tissues. This platform offers a promising strategy for targeted, TME‐modulating PDT with improved efficacy, and reduced side effects, marking a significant advance in nanodrug‐based cancer therapies.