A multifunctional biomimetic nanoplatform targeting mitochondrial dynamics and oxidative stress for heart failure therapy

Heart failure (HF) presents a significant global health challenge, caused by mitochondrial dysfunction, oxidative stress, and chronic inflammation, all of which impair cardiac function. This investigation introduces a new nanoplatform, PCM-refined M2 macrophage membrane-coated CeO 2 nanozyme loaded with PGAM5 siRNA (P-MM@Ps-CeO 2 ), that can target these interconnected disease pathways. Mechanistically, silencing PGAM5 with this nanoplatform precludes the dephosphorylation of Drp1 at Ser637, thereby lessening excessive mitochondrial fission. Yet, it restores the DDX17- BCL6 control mechanism to decrease Drp1 levels, ultimately maintaining mitochondrial balance. CeO 2 nanozymes break down reactive oxygen species (ROS), Attenuating cellular oxidative imbalance, while M2 macrophage membranes improve anti-inflammatory targeting to inflamed heart tissue, with PCM ensuring delivery precisely to the heart. In vitro, P-MM@Ps-CeO 2 re-established baseline 90% of the viability in lipopolysaccharide- worsened HL-1 cardiomyocytes, attenuated ROS by 70%, and lowered Pro-inflammatory cytokines (IL-1β, TNF-α) by up to 67%. It also preserved mitochondrial integrity, increased ATP production, and lowered apoptosis by 70%. In vivo, in a doxorubicin-induced HF mouse model, the nanoplatform improved ejection fraction to 65% and fractional shortening to 35%, reduced myocardial fibrosis by 30% and apoptosis by 70%, and increased cardiac accumulation by 2.5 times. These outcomes indicate that P-MM@Ps-CeO₂ transcends conventional HF interventions, which typically fail to address mitochondrial abnormalities. The nanoplatform showed excellent biocompatibility, with minimal hemolytic activity and no detectable organ toxicity, supporting its potential for clinical use. By simultaneously targeting mitochondrial turnover, reactive oxygen species (ROS) stress, and inflammation, P-MM@Ps-CeO 2 yields an advantageous pioneering treatment modality, HF, highly capable of improving analysis outcomes for the worldwide HF cohort. Schematic illustrating the in-situ co-precipitation of PGAM5 siRNA during CeO₂ nanozyme formation (Step 1), followed by M2 macrophage membrane coating and PCM-mediated cardiac targeting (Step 2). Schematic illustration of the therapeutic mechanism by which engineered nanozymes (P MM@Ps CeO₂) ameliorate heart failure through regulation of mitochondrial dynamics and inhibition of cardiomyocyte apoptosis