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 O₂ ) via sonodynamic effect under US irradiation, and ferroptosis inducers react with intratumoral hydrogen peroxide (H₂ O₂ ) 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.

Keywords: deep-tissue tumors; ferroptosis; immunotherapy; proteolysis-targeting chimeras (PROTACs); semiconducting polymers.