Endocytic Receptor‐Driven Self‐Assembled Lysosome Targeting Chimera Nanoplatform for Activatable Checkpoint Cancer Photo‐Immunotherapy

ABSTRACT Checkpoint immunotherapy shows great promise to treat malignancies by reinvigorating immune cells and activating antitumor immune response. However, traditional checkpoint inhibitors suffer from low response rates, poor tumor‐targeting efficiency, and drug resistance. We herein report a self‐assembled lysosome targeting chimera nanoplatform (nano‐SALTAC) with cancer‐specific endocytic receptor‐driven protein degradation for activatable checkpoint cancer photo‐immunotherapy. This nano‐SALTAC is self‐assembled from two chimeric peptides, CP LDLR , and CP PD‐L1 , which consist of the photosensitizer (protoporphyrin IX, PpIX), the cathepsin B (CatB)‐cleavable substrate, the GSGS linker, and the low‐density lipoprotein receptor (LDLR)‐/programmed cell death ligand 1 (PD‐L1)‐targeting peptides. After systemic administration, nano‐SALTAC passively targets tumor cells, drives efficient cell internalization, and induces subsequent lysosome degradation of PD‐L1 via cancer‐specific endocytic receptor LDLR. Notably, the PD‐L1 degradation efficiency is optimizable via adjusting the self‐assembly ratio of CP LDLR /CP PD‐L1 . The cancer‐overexpressed CatB further induces the disassociation of nano‐SALTAC to release the photosensitizer fragment. Under localized photoirradiation, nano‐SALTAC generates 1 O 2 to induce immunogenic cell death, thereby synergizing with PD‐L1 degradation to boost antitumor immune responses and inhibit tumor growth. Thus, such a self‐assembled LYTAC strategy provides an easily formulated nanoplatform capable of improving cancer specificity and optimizing protein degradation efficiency for cancer therapy.