Aminophosphonate-Derived Lipid Nanoparticles Enable Circular RNA Delivery for Functional Recovery after Spinal Cord...

Spinal cord injury (SCI) is a devastating neurological disorder that results in severe disability and imposes a high social and economic burden. Effective recovery from SCI requires comprehensive neural repair strategies, including neurogenesis and neuroprotection. Inspired by the structure of phospholipids in nature, we developed a library of biomimetic ionizable lipids, containing aminophosphate, aminophosphoramidate, or aminophosphonate groups (AP lipids). Then, we formulated these AP lipids into lipid nanoparticles (LNPs) and examined their mRNA delivery efficiency in neurons and astrocytes. Among these AP LNPs, AP60 LNP showed superior delivery efficiency compared to FDA approved D-Lin-MC3-DMA (MC3) LNP. To achieve longer protein expression, the circular RNA was used in LNPs. Additionally, we developed a two-step method for circular RNA production, providing a simple yet highly efficient approach. By combining these innovations, a circular RNA loaded aminophosphonate-derived lipids nanoparticles delivery system (CROSS) was constructed. To explore a therapeutic regimen, CROSS-loaded with circular Sox2, Ascl1, and GDNF RNAs were administered locally and intravenously in SCI model, which led to the restoration of bladder function and significant motor function recovery. In summary, the CROSS platform provided a novel and effective strategy for treating SCI.