Photoactivatable Silencing Extracellular Vesicle (PASEV) Sensitizes Cancer Immunotherapy

Abstract Immunotherapy has delivered impressive outcomes in combating tumor malignancies. However, insufficient immune infiltration and poor immunogenicity within the tumor microenvironment (TME) greatly compromise patient response rates. Here, a photoactivatable silencing extracellular vesicle (PASEV) is developed for sensitized cancer immunotherapy. p21‐Activated kinase 4 (PAK4) is a newly identified tumor‐cell‐intrinsic “guard” associated with immune exclusion. Small interfering RNA against PAK4 (siPAK4) is designed and assembled with a photoactivatable reactive‐oxygen‐species (ROS)‐sensitive polymer to form the nanocomplex core, which is further camouflaged by extracellular vesicles from M1 macrophages. The PASEV not only serves as a vehicle for packaging, tumor accumulation, and ROS‐responsive release of siPAK4 for potent PAK4 silencing, but also primes the TME through immunogenic phototherapy, thereby simultaneously boosting intratumoral infiltration and immune activation. The combined immunotherapy elicits robust anticancer immunity, thus showing great promise for fighting cancers. This work opens a new avenue to simultaneously boost intratumoral infiltration and immune activation for sensitized cancer immunotherapy.