RNA therapeutics hold transformative potential across a range of diseases, but effective and safe delivery remains the primary obstacle to broader clinical application. Traditional lipid nanoparticles (LNPs) are highly effective yet constrained by off-target effects, immunogenicity, and narrow biodistribution profiles. To address these limitations, we have developed a new class of whole-cell lipid nanoparticles (WCLNPs), derived from the lipid extracts of various mammalian cell types.
The WCLNP platform leverages the compositional complexity of natural lipidomes to impart innate biological properties—such as enhanced biocompatibility, immune invisibility, and cell-specific uptake—while retaining the modularity and synthetic control of conventional LNPs. By formulating WCLNPs with ionizable and PEGylated lipids, we have created a tunable delivery system that can encapsulate a variety of RNA cargos, including mRNA and siRNA.
A diverse library of WCLNPs was synthesized from hepatocytes, macrophages, epithelial cells, and fibroblasts. In vitro studies showed cell-of-origin-dependent uptake patterns, with epithelial-derived WCLNPs showing enhanced delivery to epithelial lines, and macrophage-derived WCLNPs demonstrating selective uptake by immune cells. In vivo biodistribution following intravenous injection confirmed distinct tissue accumulation profiles, suggesting organ-selective delivery potential based on lipid source.
This natural lipid-based strategy provides a unique path to engineer LNPs with tailored biodistribution and cellular tropism without the need for complex ligand conjugation. WC-LNPs offer particular promise for RNA delivery to hard-to-reach tissues or immune-privileged sites, as well as for applications requiring repeated dosing with minimal immunogenicity
Looking ahead, the WCLNP platform serves as a flexible foundation for RNA therapeutics in infectious disease, cancer, inflammation, and beyond. Ongoing work includes high-throughput screening of WCLNP libraries and integration with disease-specific RNA cargos to match biodistribution profiles with therapeutic needs.
This bioinspired approach opens new possibilities for rational design of targeted, non-immunogenic RNA delivery systems that bridge the best of synthetic and natural nanoparticle technologies.