NIR Emissive Functional Nanoparticles Promote Precise Pancreatic Cancer Therapy by Co-Targeting Mutant p53 and Oncogenic KRAS

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable global health challenge. Targeting genetic aberrations, particularly KRAS and TP53 mutations, remains a critical challenge in PDAC treatment. Herein, it is demonstrated for the first time that electron-rich aromatic pyrrole derivatives can be transformed into red-to-near-infrared emissive radical cations in an acidic buffer, efficiently targeting mitochondria and triggering mutant p53 (mutp53) degradation. Leveraging the positive charge characteristic of radical cations (P6 ^•+ ), a bifunctional nanoparticle is successfully engineered by combining P6 ^•+ with KRAS siRNA. P6@siKRAS simultaneously induces mutp53 degradation and the oncogenic KRAS downregulation, thereby abrogating gain-of-function effects by mutp53 and inhibiting downstream signaling pathways regulated by KRAS, leading to significant suppression of tumor growth, invasion, and drug resistance. Consequently, P6@siKRAS demonstrates remarkable therapeutic efficacy in both the p53-KRAS-double-mutated pancreatic cancer model and the LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre (KPC) mice model. Moreover, the down-regulation of mutp53 and KRAS by P6@siKRAS not only inhibits tumor growth but also substantially remodels the tumor microenvironment, recruiting and boosting the infiltration of anti-tumor immune cells, thereby augmenting the anti-tumor immune response. This study showcases the development of mutp53-degrading functional gene carriers, offering a promising and innovative therapeutic strategy for tackling p53-KRAS-double-mutated pancreatic cancer.