A lipoprotein-biomimetic nanoplatform for oncogenic KRAS mutation-specific lysosome-targeting protein degradation

Lysosome-targeting protein degradation strategies have evolved to leverage lineage-specific receptors to improve selectivity, yet remain unable to distinguish malignant from normal cells within the same lineage. Since oncogenic mutations are the defining feature of malignant cells, we here develop KRAS-mutated (MT) tumor targeting chimeras (KRASTAC), a lipoprotein-biomimetic nanoplatform that hijacks the enhanced macropinocytosis in KRAS-MT cells for mutation-specific protein degradation. KRASTAC potently degrades diverse proteins including epidermal growth factor receptor and programmed cell death ligand 1 (PD-L1) in KRAS-MT cells at a low antibody concentration of 2.5 nM within 9 h, with minimal impact in KRAS wild-type (WT) cells. Furthermore, KRASTAC exhibits mutation-specific tumor accumulation and protein degradation in vivo. KRASTAC-induced PD-L1 degradation leads to robust antitumor efficacy and reprogramming of the immunosuppressive microenvironment in mice carrying Kras-MT tumors. Our work presents KRASTAC as a potent mutation-specific protein degradation strategy for KRAS-MT cancers and establishes macropinocytosis as a route for lysosome-targeting protein degradation.