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

Abstract 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.