Targeted CRISPR-Cas9 Delivery via Biodegradable Polymeric Nanoparticles for Precision Oncogene Inactivation in Solid Tumors

Despite the therapeutic potential of CRISPR-Cas9 genome editing in oncology, clinical translation is constrained by off-target toxicity, immunogenicity, and inefficient systemic delivery to solid tumors. This study reports the development and characterization of lipid-anchored poly(lactic-co-glycolic acid) (PLGA) nanoparticles engineered for the selective, high-affinity co-delivery of Cas9 ribonucleoprotein complexes and guide RNAs targeting the KRAS oncogene. The formulated nanoparticles exhibited a uniform hydrodynamic diameter of 115 nm, sustained stability in physiological serum, and rapid endosomal escape kinetics. In vitro assays on human non-small cell lung cancer cell lines demonstrated an on-target editing efficiency of 81.3% with undetectable non-specific cleavage at predicted homologous loci. In orthotopic murine tumor models, intravenous administration of the nano-formulation resulted in significant tumor volume reduction of 68.5% over a 28-day regimen without systemic biomarker toxicity. These findings highlight a viable non-viral nano-carrier platform for safe, targeted gene editing in refractory oncological conditions.