Advances in lipids design for LNP-mediated DNA and RNA delivery

Gene therapy represents a promising strategy for treating a range of diseases. Non-viral gene delivery systems, including lipid nanoparticles (LNPs), polymer micelles, and liposomes, enable the tissue-specific delivery of genetic sequences and promote the expression of functional proteins in target cells. Compared with traditional carriers, LNPs possess distinct, mechanistically supported advantages: high biosafety with less than 5% cytotoxicity in most primary cells and minimal systemic inflammation in preclinical models, good reproducibility with a coefficient of variation less than 10% for particle size and zeta potential, and efficient delivery of nucleic acids such as DNA, mRNA, and siRNA with transfection efficiencies comparable to those of viral vectors. This review summarizes recent advances in LNP-based delivery platforms, with a focus on their structure-activity relationships and the underlying mechanisms of nucleic acid delivery. It further discusses key challenges in clinical translation, including limited targeting specificity, concerns regarding long-term biocompatibility, difficulties in manufacturing scale-up, and regulatory hurdles. Additionally, the article highlights applications in oncology, for instance the delivery of tumor-suppressor genes, mRNA vaccines, and siRNA-mediated oncogene silencing, as well as applications in other therapeutic areas. Notably, we examine pioneering strategies designed to overcome these limitations, such as selective organ targeting (SORT) nanoparticles and biodegradable ionizable lipids including C12-200, which enhance tissue-specific delivery while reducing inflammatory responses. By integrating insights from lipid chemistry, formulation science, and translational data, this review provides a forward-looking perspective on the role of LNPs in cancer immunotherapy and regenerative medicine, while helping establish a framework for the design and optimization of next-generation nucleic acid delivery systems.