Biomimetic systems for improving delivery of RNA therapeutics

Biomimetic hybrid systems have emerged as promising strategy to combine the controllable features of synthetic nanocarriers with the biological functionality of natural membranes, with the aim to improve targeted delivery of therapeutics. Here, biomimetic hybrid systems refer to synthetic nanocarriers endowed with selected biological components to potentially confer native‑like recognition, trafficking, or immune‑stealth properties. For instance, EV-polymer hybrids combine the condensation capacity of PEI-based polyplexes with the biological properties of EVs to enhance RNA delivery in prostate cancer models. Furthermore, mRNA-LNPs hybridized with plasma-membrane-derived nanovesicles have shown markedly improved intracellular trafficking and higher protein expression, highlighting how cell-derived vesicles can overcome intrinsic limitations of synthetic systems. In addition, liposomes functionalized with cell-derived membrane proteins have yielded hybrid nanovesicles with neuron-targeting capacity, while EV-liposome
hybrids produced by lipid-film hydration followed by extrusion have enabled siRNA encapsulation and functional gene silencing, together showing how biological membrane integration can confer unique properties that enhance cell recognition and interactions as compared to conventional liposomes. However, despite these encouraging advances, potential research avenues remain largely unexplored.
Current EV-polymer hybrids have been studied for siRNA delivery, leaving it unclear whether such systems can be extended to larger and more complex RNA molecules such as mRNA. Likewise, while liposomes functionalized with cell-derived membrane proteins have demonstrated enhanced targeting, their evaluation has not extended to EV-derived membrane proteins, leaving open the question of whether EVs could provide additional advantages for therapeutic delivery.

Altogether, this thesis investigates how different biomimetic hybrid systems ranging from EV-polymer complexes to membrane-functionalized lipid nanoparticles and liposomes can expand the functional landscape of RNA delivery, offering insights into their opportunities, limitations, and potential as next-generation drug delivery platforms.