Discovery of an HSP90-Modulating Amphiphilic Peptide Dendrimer as a Bioactive Carrier for Combination Cancer Therapy.

Conventional single-target drugs frequently suffer from limited efficacy and drug resistance. Here, we report an amphiphilic peptide dendrimer that integrates intrinsic bioactivity and nanocarrier functions, establishing a novel "drug-bioactive carrier" paradigm for multi-target cancer therapy. Using reverse molecular docking and limited proteolysis-mass spectrometry (LiP-MS), heat shock protein 90 (HSP90) was identified as a prominent candidate intracellular target of the dendrimer. Structure-activity relationship studies revealed that amphiphilic balance and dendrimer topology govern self-assembly and HSP90 modulation, with C16-KK2 displaying optimal activity by disrupting HSP90-CDC37 interaction and promoting degradation of oncogenic client proteins. Importantly, C16-KK2 nanoassemblies effectively encapsulate hydrophobic anticancer drugs, enhancing intracellular delivery and yielding synergistic therapeutic effects with rapamycin and sorafenib. In vivo, sorafenib-loaded C16-KK2 nanoparticles exhibited superior tumor accumulation and enhanced antitumor efficacy compared to free drug treatment. This work presents a mechanistically defined and structurally feasible bioactive nanocarrier platform, advancing rational design strategies for multi-target cancer therapeutics.