Lipid nanoparticle-mediated co-delivery of human RB1 mRNA and triptolide for localized genetic therapy of retinoblastoma.
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Retinoblastoma is a rare pediatric intraocular malignancy for which intravitreal administration offers a clinically attractive route for localized therapy owing to its minimally invasive nature and direct access to intraocular tumors. However, efficient intravitreal delivery of nucleic acids remains challenging because the protein-poor vitreous microenvironment restricts nanoparticle transport and subsequent intracellular delivery. Conventional lipid nanoparticles (LNPs), which have been primarily developed for systemic administration, are therefore not necessarily suited to this unique biological environment. Here, we developed a C12-200-containing lipid nanoparticle (CLNP) engineered for efficient intravitreal gene delivery through systematic optimization of lipid composition. The optimized CLNP exhibited favorable diffusion within the vitreous, efficient intracellular mRNA delivery, and reduced dependence on extracellular protein-assisted uptake under vitreous-mimetic conditions. To demonstrate the therapeutic versatility of the platform, human RB transcriptional corepressor 1 mRNA and triptolide were co-delivered as representative gene and small-molecule therapeutics. CLNP-mediated co-delivery of hRB1 mRNA and triptolide produced greater antiproliferative activity than either monotherapy in vitro and markedly suppressed tumor progression in an orthotopic retinoblastoma model following a single intravitreal administration, with no detectable abnormalities in retinal function, structure, or apoptosis during the evaluation period. Collectively, this study establishes a vitreous-oriented lipid engineering strategy that simultaneously improves extracellular transport through the vitreous and intracellular nucleic acid delivery, providing a broadly applicable platform for localized gene delivery and combination gene-drug therapy for ocular diseases.