Cytomembrane-targeted photodynamic priming triggers extracellular vesicle storm for deep penetration and complete destruction of bladder cancer

The overexpressed extracellular matrix and elevated interstitial fluid pressure in tumor extremely restricts deep infiltration of nanomedicines, which makes poor penetration an unsolved problem for potent antitumor drug delivery. It has been demonstrated that sub-cytotoxic photodynamic priming (PDP) could disrupt and permeabilize extracellular matrix to promote the tumor penetration of nanotherapeutics. However, given high interstitial fluid pressure, the efficacy is always limited owing to the passive diffusion of huge nanoparticles. Here, we, for the first time, find that cytomembrane-targeted PDP can effectively induce extracellular vesicle (EV) storm to enable intercellular transport of azide-containing ligands for active spread throughout the whole tumor, and thereafter destroy the entire tumor via bioorthogonal reaction. The membrane fusogenic liposome incorporating azide lipids is designed to encapsulate aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photosensitizer TSSI. Following tumor accumulation, both azide ligands and TSSI could be transported to the cancer cell membrane and further packaged into the membrane of EVs. Under laser irradiation, PDP activates calcium channels on the cytomembrane via reactive oxygen species (ROS)-dependent thiol oxidation to boost cytosolic calcium influx, which is the main inducer of EVs. Endogenous EVs generated by outer layer cells provoke the intercellular delivery of azide ligands and TSSI into deep regions layer-by-layer. Then, the dibenzocyclooctyne (DBCO)-doxorubicin conjugate is intravenously administrated, which can effectively, selectively, and irreversibly react with azide lipids on the cell surface via bioorthogonal chemistry, allowing facilitated drug penetration and excellent therapeutic outcomes.