Biomaterials-guided nanomedicine for familial adenomatous polyposis: lipid nanopartiscle RNA therapeutics with translational relevance.

Familial adenomatous polyposis (FAP) is a genetic disorder primarily driven by mutations in the adenomatous polyposis coli (APC) gene, leading to hereditary colorectal cancer. Without intervention, FAP almost invariably progresses to colorectal carcinoma. Due to the large molecular weight of APC protein, traditional drugs fail to restore its function. In this study, we conducted a statistical analysis of APC gene mutations, optimizing key functional peptide sequences for therapeutic delivery. Using a clinically validated ionizable lipid-based lipid nanoparticle (LNP) formulation, we reproduced, prepared, and characterized messenger RNA (mRNA)-loaded LNPs designed to deliver therapeutic peptides while avoiding integration risks. Dynamic light scattering (DLS) was used to measure particle size, and RiboGreen assay determined encapsulation efficiency. Mechanistically, we confirmed cellular uptake and cytoplasmic expression through immunofluorescence confocal microscopy. In vivo, the mRNA-LNP formulation was administered via intraperitoneal (IP) injection in APC mice, with in vivo imaging conducted at 4 weeks to verify the feasibility of intestinal delivery. The formulation demonstrated significant prevention of adenoma burden in APC mice, accompanied by β-catenin nuclear exclusion, downregulation of c-Myc/AKT1/MMP9, and restoration of zonula occludens-1 (ZO-1) membrane localization. Immunocompatibility and safety were supported by cytokine, complement, liver and kidney function assays, and histopathological analysis. Based on our experimental data, we propose a translational pathway, from preclinical intraperitoneal validation to clinically feasible local delivery (e.g., endoscopic submucosal injection or retention enema), with dose translation and follow-up endpoint suggestions. This study demonstrates the potential of advanced biomaterials and nucleic acid therapeutics for genetic/rare diseases, providing a basis for personalized FAP prevention.