Abstract Body: [Background]
Delivering siRNA therapeutics to the heart is a major challenge. Most conventional lipid nanoparticles (LNPs) are rapidly cleared by the liver before they can reach the myocardium. This hepatic sequestration precludes effective cardiac accumulation and overall therapeutic efficacy.
[Hypothesis]
We hypothesized that camouflaging LNPs with macrophage-derived membranes would induce immune tolerance against liver Kupffer cells. This biological camouflage would allow the hybrid LNPs to bypass the hepatic filter, prolonging systemic circulation for enhanced cardiac uptake.
[Aims]
The goal of this study was to develop a dual-function biomimetic nanoplatform. By integrating the nucleic acid delivery of LNPs with the natural stealth of host cell membranes, we sought to enable both systemic evasion and active cardiac targeting within a single hybrid system.
[Methods]
To achieve this, siRNA-loaded LNPs were hybridized with M2-like macrophage-derived nanovesicles (M2NV). The surface was then functionalized with a cardiac-targeting peptide (CTP) to formulate CTP-hLNPs. For efficacy confirming, we loaded siRNA targeting RUNX1(siRUNX1), a factor of cardiac fibrosis.
[Results]
Biodistribution analysis confirmed the validity of this design. Compared to standard peptide-modified nanoparticles, the M2NV-LNP hybrid effectively avoided hepatic uptake and significantly enhanced cardiac delivery. In an angiotensin II-induced mouse model, this formulation successfully suppressed siRUNX1 pro-fibrotic signals and also inhibited α-SMA and collagen I/III production, thereby inhibiting fibrosis, restoring cardiac function, and delaying pathological remodeling.
[Conclusion]
This hybridization strategy directly addresses the primary obstacle in cardiac gene therapy by merging biomimetic camouflage with active targeting. It provides a highly adaptable and realistic platform for targeted nucleic acid delivery.