Dual‐Programmable Semiconducting Polymer NanoPROTACs for Deep‐Tissue Sonodynamic‐Ferroptosis Activatable Immunotherapy

Abstract Proteolysis‐targeting chimeras (PROTACs) can provide promising opportunities for cancer treatment, while precise regulation of their activities remains challenging to achieve effective and safe therapeutic outcomes. A semiconducting polymer nanoPROTAC (SPN FeP ) is reported that can achieve ultrasound (US) and tumor microenvironment dual‐programmable PROTAC activity for deep‐tissue sonodynamic‐ferroptosis activatable immunotherapy. SPN FeP is formed through a nano‐precipitation of a sonodynamic semiconducting polymer, a ferroptosis inducer, and a newly synthesized PROTAC molecule. The semiconducting polymers work as sonosensitizers to produce singlet oxygen ( 1 O 2 ) via sonodynamic effect under US irradiation, and ferroptosis inducers react with intratumoral hydrogen peroxide (H 2 O 2 ) to generate hydroxyl radical (·OH). Such a dual‐programmable reactive oxygen species (ROS) generation not only triggers ferroptosis and immunogenic cell death (ICD), but also induces on‐demand activatable delivery of PROTAC molecules into tumor sites. The effectively activated nanoPROTACs degrade nicotinamide phosphoribosyl transferase (NAMPT) to suppress tumor infiltration of myeloid‐derived suppressive cells (MDSCs), thus promoting antitumor immunity. In such a way, SPN FeP mediates sonodynamic‐ferroptosis activatable immunotherapy for entirely inhibiting tumor growths in both subcutaneous and 2‐cm tissue‐covered deep tumor mouse models. This study presents a dual‐programmable activatable strategy based on PROTACs for effective and precise cancer combinational therapy.