Lipid nanoparticles (LNPs) have emerged as a clinically validated nonviral RNA delivery system. However, their limited tumor targeting remains challenging in oncology. In this work, LNPs were functionally integrated with cancer cell membrane components to enhance their targeting capabilities. The natural composition of tumor membranes was leveraged to promote both homotypic and heterotypic adhesion, exploiting cancer cell self-recognition and interactions with stromal cells in the tumor microenvironment. A biomimetic nanocarrier was developed by cloaking RNA-loaded LNPs with nanoghosts obtained from the membrane of triple negative breast cancer cells. Nanoghosts were dye-labeled and comprehensively characterized in terms of size, surface charge, protein composition, and membrane sidedness. The functional orientation of nanoghost membrane-associated proteins mediated homotypic binding with 4 T1 cells and heterotypic recognition of functionally validated cancer-associated fibroblasts and exhibited higher affinity for the latter, as confirmed through flow cytometry and confocal microscopy. RNA-LNPs were incorporated into nanoghosts using ultrasound-assisted fusion, yielding stable biomimetic LNPs with a multilamellar mRNA-LNP core enveloped by a nanoghost shell, as confirmed by Small-Angle X-ray Scattering. While uncoated LNPs showed negligible interaction with heterotypic cells, biomimetic LNPs displayed strong affinity for cancer-associated fibroblasts, enabling efficient internalization and RNA transfection. Additionally, the biomimetic coating enhanced LNP uptake in homotypic 4 T1 cells, resulting in significantly improved biological activity compared to uncoated LNPs. This work provides proof of concept that RNA-LNPs can be effectively integrated into biomimetic carriers to enable dual targeting of tumor and stromal cells. The enhanced selectivity and delivery performance of biomimetic LNPs highlight their therapeutic potential for overcoming stromal barriers in desmoplastic tumors such as triple negative breast cancer.
