A self-assembled hydrophobic polymer tagged nanoplatform for membrane protein degradation and immunomodulatory drug...

Targeted protein degradation (TPD) has emerged as a powerful strategy for eliminating disease-driving proteins, yet its broader application remains constrained by limited target specificity and the lack of integrated therapeutic delivery functions. Here, we report Tri@N, a multimodal polymeric nanoplatform that extends hydrophobic polymer-based TPD to membrane-associated targets while simultaneously enabling immunomodulatory drug delivery. Tri@N is engineered to remain stable during systemic circulation but undergo intracellular disassembly in response to elevated GSH levels. This disassembly exposes hydrophobic polymer segments that function as a hydrophobic polymer tag, promoting EGFR destabilization and degradation through both proteasomal and autophagy-lysosomal pathways. In parallel, Tri@N releases niclosamide (NIC), which suppresses the STAT3/PD-L1 signaling axis. In colorectal cancer models, Tri@N achieved coordinated EGFR degradation and PD-L1 downregulation, resulting in enhanced CD8⁺ T cell-mediated antitumor immunity and robust tumor suppression in vivo. These findings establish Tri@N as a dual-functional polymeric nanoplatform that integrates hydrophobic polymer tagging-mediated degradation of a membrane protein with therapeutic payload delivery, providing a versatile strategy for multimodal cancer therapy.