Two‐Step Targeting‐Tunable Semiconducting Nanoswitches Amplify Mitochondrion Damage and PD‐L1 Blockade for Orthotopic Pancreatic Cancer Therapy

Abstract Pancreatic cancer is a malignancy tumor with luxuriant extracellular matrix (ECM) and highly immunosuppressive microenvironment and its therapy remains an enormous challenge. A two‐step targeting‐tunable strategy is proposed for orthotopic pancreatic cancer therapy via designing semiconducting nanoswitches (C/SPN T /αP) to amplify the mitochondrion damage and programmed death ligand 1 (PD‐L1) blockade. A mitochondrion‐targeting small nanoparticle (SPN T ) consisting of mitochondrial targeting moiety triphenylphosphine (TPP) and semiconducting polymer is embedded with PD‐L1 antibody (αPD‐L1) into sono‐responsive collagen binding peptide (CBP)‐conjugated nanoliposomes to form C/SPN T /αP. In the first targeting step, C/SPN T /αP achieve ECM targeting to observably increase their enrichment into orthotopic pancreatic tumor sites because CBP can effectively bind to collagen in ECM. Upon ultrasound (US) irradiation, C/SPN T /αP mediate a sono‐responsive structural failure via sonodynamic effect for on‐demand releases of SPN T and αPD‐L1. In the second targeting step, SPN T target to mitochondria to induce mitochondrial damage under US irradiation for triggering amplified cell apoptosis and immunogenic cell death (ICD). Moreover, the released αPD‐L1 blocks the immunosuppressive pathway to further boost immunological effect. Such a novel therapeutic regimen can almost completely eradicate orthotopic pancreatic Panc02 and KPC tumors in mouse models. This study presents the first two‐step targeting‐tunable nanomedicine for treatments of deep‐seated orthotopic tumors.