Bioactive lipid-derived nanoparticles for RNA delivery

Lipid nanoparticles (LNPs) have emerged as the most widely used and clinically validated platform for delivering RNAs, including small interfering RNA (siRNA) and messenger RNA (mRNA), as exemplified by the FDA approvals of Onpattro, Comirnaty, Spikevax, and mRESVIA. LNPs offer various benefits for RNA delivery, such as protecting RNA from enzymatic degradation, increasing cellular uptake and endosomal escape, and improving pharmacokinetics. To further broaden their use across a wide spectrum of diseases, various LNPs have recently been developed with unique biological functions, such as immunomodulation, tissue microenvironmental modulation, endosomal pathway interference, pharmacological activity, and tissue and cell selectivity, giving rise to the emerging concept of bioactive lipid-derived nanoparticles (bioactive LNPs). In this review, we summarize bioactive LNPs incorporating naturally sourced bioactive lipids, bioactive agent-derived lipids, or novel bioactive lipids identified through combinatorial synthesis coupled with high-throughput screening. We also discuss the structure-activity relationship of these bioactive lipids and overview their corresponding LNPs for specific biomedical applications. We further provide perspectives on the challenges and opportunities in translating bioactive lipid-derived LNPs into next-generation RNA nanomedicines.