Responsive Degradable Bottlebrush Polymers Enable Drugs With Superior Efficacy and Minimal Systemic Toxicity.

Bottlebrush polymers (BBPs) have garnered significant attention as advanced drug delivery systems, capable of transporting a diverse range of therapeutic agents, including both chemical drugs and biologics. Despite their effectiveness, the empty BBP vectors post-drug release may pose long-term safety risks due to their difficult systemic clearance. Here, a responsive degradable BBP platform for cancer therapy is developed, featuring a poly(disulfide) backbone grafted with fluorine-terminated zwitterionic side chains. Anti-cancer drugs are tethered to the backbone via a clinically approved valine-citrulline (VC) linker. This design leverages the tumor's reductive environment and Cathepsin B overexpression for BBP rapid degradation and precise drug release restricted within tumor cells, thereby addressing systemic safety concerns over synthetic BBP and expanding the therapeutic window of anti-cancer drugs simultaneously. Surface fluorination of BBP further enhances tumor accumulation and deep penetration. In vivo studies with monomethyl auristatin E (MMAE)-loaded BBP in tumor-bearing mice demonstrate substantial tumor suppression with minimal side effects. Together, these findings highlight the potential of responsive degradable BBP as a versatile unimolecular platform for cancer drug delivery, addressing existing challenges associated with synthetic BBP nanomedicines.