Tumor microenvironment-activated ferritin nanovector enables enhanced tumor delivery of KRAS inhibitors and degraders.

Mutations in RAS oncogenes (KRAS, HRAS, NRAS) are among the most common genetic alterations in human cancers. The activating KRAS mutation, in particular, is a key driver in a significant percentage of non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and lung adenocarcinoma. While KRAS was long considered undruggable, the development of mutant-specific inhibitors, including covalent inhibitors targeting KRAS (such as Sotorasib and Adagrasib) and non-covalent inhibitors targeting KRAS (such as Mirati's MRTX1133), has shown promise. These inhibitors function by binding to a shallow pocket between the switch-I and switch-II elements, locking KRAS in its inactive GDP-bound state. However, concerns exist regarding the efficacy and the development of resistance to Sotorasib and Adagrasib through mechanisms like secondary mutations, KRAS overexpression, and KRAS downstream pathway activation. To overcome these limitations, we developed a novel, stimuli-sensitive, tumor microenvironment-activated, ferritin-derived nanomedicine platform, named The-05. This platform, previously shown to effectively enhance payload biodistribution, plasma half-life, and reduce off-target effects in various tumors, is reported here to: 1) encapsulate high amounts of the KRAS inhibitor Adagrasib and the PROTAC degrader LC-2; 2) to achieve efficient intracellular delivery , once activated by matrix metalloproteases MMP-2 and MMP-9. In cellular models of KRAS-mutated NSCLC and PDAC, this nanoplatform achieved comparable or superior therapeutic outcomes with respect to the individual drugs. This study provides a compelling proof-of-concept for the delivery of KRAS mutant-specific inhibitors and degraders to human tumors through a tumor microenvironment-activated nanomedicine approach and lays the groundwork for future studies in physiologically relevant models to assess TME-specific activation and tumor selectivity.