A Cascade‐Targeted Enzyme‐Instructed Peptide Self‐Assembly Strategy for Cancer Immunotherapy through Boosting Immunogenic Cell Death

Immunogenic cell death (ICD) approaches by encumbering mitochondrial functions provide great promise for the treatment of malignant tumors, but these kinds of ICD strategies are still in their infancy. Here, one multifunctional drug‐loaded, cascade‐targeted, and enzyme‐instructed self‐assembling peptide nanomedicine (Comp. 4) for ICD‐based cancer therapy is constructed. Comp. 4 consists of 1) lonidamine (LND) that specifically interferes with mitochondrial functions; 2) a programmed death ligand 1 (PD‐L1) binding peptide sequence (NTYYEDQG) and a mitochondria‐specific motif (triphenylphosphonium, TPP) that can sequentially control the cell membrane and mitochondria targeting capacities, respectively; and 3) a ‐GDFDFpDY‐ assembly core to in situ organize peptide assemblies responsive to alkaline phosphatase (ALP). Comp. 4 demonstrates noticeable structural and morphological transformations in the presence of ALP and produces peptide assemblies in mouse colon cancer cells (CT26) with high expressions of both ALP and PD‐L1. Moreover, the presence of PD‐L1‐ and mitochondria‐specific motifs can assist Comp. 4 for effective endocytosis and endosomal escape, forming peptide assemblies and delivering LND into mitochondria. Consequently, Comp. 4 shows superior capacities to in vivo induce abundant mitochondrial oxidative stress, provoke robust ICD responses, and produce an immunogenic tumor microenvironment, successfully inhibiting CT26 tumor growth by eliciting a systemic ICD‐based antitumor immunity. A multifunctional immunogenic cell death (ICD) inducer loaded with lonidamine (LND) is constructed. The cascade‐targeted capacities against programmed cell death ligand 1 and mitochondria guide the inducer to interact with mitochondria accurately, producing peptide assemblies and delivering LND into mitochondria. The inducer successfully provokes mitochondrial oxidative stress, ICD responses, and an abundant ICD‐based immunity to prevent tumor growth.