Lipid nanoparticle platforms for p53-targeted cancer therapy

Lipid nanoparticles (LNPs) have emerged as the most clinically validated nanocarrier platform in oncology, transitioning from liposomal chemotherapy to the cornerstone of mRNA-based therapeutics. This review critically examines the evolving LNP landscape with a deliberate focus on p53, the tumour suppressor directly mutated or functionally silenced via pathway dysregulation in over half of human cancers and a unifying therapeutic target across diverse tumour types. We analyse LNP platform design, physicochemical properties, and structure-activity relationships that govern encapsulation, stability, and release. A dedicated section synthesizes p53-directed nucleic acid strategies delivered by LNPs, including p53 mRNA for wild-type restoration, siRNA for mutant p53 silencing, miR-34a mimics engaging the p53 downstream axis, and CRISPR-Cas9 components for TP53 correction. The review evaluates passive and active targeting, stimuli-responsive release mechanisms responsive to tumour microenvironmental cues, and the integration of p53 nanotherapy with immune checkpoint blockade. Clinical translation is appraised through key 2020–2026 milestones, notably the KEYNOTE-942 trial of personalized neoantigen mRNA-4157, which clinically validates the mRNA-LNP platform in oncology, alongside emerging preclinical and early exploratory p53 mRNA-LNP programs in hepatocellular carcinoma, non-small cell lung cancer, and pancreatic cancer. Persistent challenges, including liver-dominant biodistribution, anti-PEG immunogenicity, manufacturing scalability, and regulatory complexity, are discussed alongside artificial intelligence-guided lipid discovery and biomimetic approaches. By reframing LNP development around p53 biology, this review highlights how tumour-suppressor restoration offers a mechanistically coherent strategy to enhance therapeutic index, reprogram the tumour immune microenvironment, and extend LNP clinical benefit beyond the liver compartment across diverse tumour types. The synthesis indicates that p53-focused LNP engineering represents a convergent opportunity to unify diverse cancer nanomedicine efforts under a single, biologically grounded therapeutic paradigm.