Achieving the goldilocks zone of lung-targeted mRNA delivery with a charge-steric optimized quantum dot-lipid system
Lin Wang1, Jianyu Wang1, Zhongxing Xu1
1Academy of Military Medical Sciences, No. 27 Taiping Road, Haidian District, Beijing 100850, PR China.
Abstract:
The treatment of pulmonary diseases via nucleic acid drugs faces major challenges in targeting specificity and transfection efficiency. While messenger RNA (mRNA) therapeutics hold great potential, their clinical translation requires advanced delivery systems. In this study, inspired by first-principles thinking-deconstructing the mRNA delivery process to its fundamental physicochemical requirements-a simplified lipid system for lung-targeted mRNA delivery was constructed, using the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) for lung targeting, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) for enhancing biosafety via steric hindrance and alanine-derived carbon quantum dots (Ala-CQDs) for further enhancing transfection efficiency. Comprehensive safety evaluations confirmed that DSPE-PEG2000 effectively reduced DOTAP-induced cytotoxicity, hemolysis, coagulation dysfunction, and organ damage. Mechanistic studies revealed that Ala-CQDs enhance lung-targeting and transfection efficiency through formation of a lung-tropic protein corona and promotion of endolysosomal escape. Compared with the reported lung-selective organ-targeting lipid nanoparticle (Lung-SORT LNP), the streamlined delivery system-retaining only functionally essential components-not only yielded an approximately 40-fold increase in lung-targeted transfection efficiency but also exhibited markedly improved biocompatibility and reduced toxicity. The system enabled the co-loading of matrix metalloproteinase 13 (MMP13) mRNA and the tyrosine kinase inhibitor nintedanib (Nin) to formulate the nanomedicine mMMP13@Lipo(Nin)/Ala-CQDs. As a combination regimen for pulmonary fibrosis, it proved effective in promoting collagen degradation, restoring lung function, and mitigating alveolar damage. Collectively, this work establishes a streamlined yet potent and biosafe lipid system, providing a novel strategy for mRNA-based therapy for pulmonary diseases.
