Reprogrammed macrophage-derived nanovesicle-lipid nanoparticle hybrids for cardiac siRUNX1 delivery: Therapeutic evaluation in Ang II-induced cardiac remodeling

Targeted delivery of small interfering RNA (siRNA) to the heart remains challenging because conventional lipid nanoparticles (LNPs) predominantly accumulate in the liver following systemic administration. To improve cardiac siRNA delivery, we developed a biomimetic hybrid nanoplatform by co-extruding siRUNX1-loaded LNPs with reprogrammed macrophage-derived nanovesicles (rMNVs) obtained from sequentially LPS/TGF-β1-treated RAW264.7 macrophages, followed by surface functionalization with a cardiac-targeting peptide (CTP). The sequentially treated donor cells exhibited a phenotypic shift characterized by reduced M1-associated markers and enhanced M2-associated features. The resulting CTP-hLNPs maintained a nanoscale spherical morphology, high siRNA encapsulation efficiency, and retained donor-cell-derived membrane components, including CD206. In vitro, CTP-hLNPs showed reduced uptake by RAW264.7 macrophages while maintaining cellular internalization and siRUNX1 activity in H9c2 cardiac-derived cells. Following intravenous administration, CTP-hLNPs exhibited reduced liver-associated fluorescence and increased heart-associated fluorescence at 24 h compared with conventional CTP-LNPs. Therapeutic efficacy was subsequently evaluated in an angiotensin II (Ang II)-induced mouse model of cardiac remodeling. CTP-hLNP@siRUNX1 reduced cardiac RUNX1 mRNA expression and improved left ventricular systolic function, as indicated by increased left ventricular ejection fraction and fractional shortening. Treatment also attenuated cardiac hypertrophic remodeling, including reductions in the heart weight-to-body weight ratio and cardiomyocyte cross-sectional area. In addition, CTP-hLNP@siRUNX1 reduced myofibroblast-associated α-SMA expression, collagen deposition, and myocardial fibrotic area. Collectively, these findings support rMNV-LNP hybridization combined with CTP functionalization as a potential delivery strategy for cardiac RNA interference therapy and demonstrate its therapeutic effects in Ang II-induced cardiac remodeling.

Abstract from PubMed Central (PMID 43022900, PMC13756362). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.