Synergistic prohibitin-targeted microRNA-resveratrol nanotherapy effectively reverses obesity in high-fat obese mice.

Available treatments for obesity face hurdles due to severe side effects, off-target effects, and compromised cellular uptake, highlighting the need for an effective alternative therapy. The rationale of this work is to explore prohibitin-targeted proton sponge nanovesicles with a regulatory microRNA-resveratrol cocktail (@T-miR-RES-PPNVs; 171.6 ± 5.88 nm particle size and + 16.8 ± 0.76 mV zeta potential) to efficiently combat obesity. The developed NVs efficiently encapsulated miR-130b employing the dendron-complexation phenomenon as well as protecting against RNase degradation. In vitro biocompatibility testing confirmed the safety of the formulation. The biological efficacy of @T-miR-RES-PPNVs inferred efficient downregulation of adipogenic and the upregulation of metabolic mRNA and protein markers. Furthermore, pharmacodynamic parameters, supported by histopathological and hematological studies, ensured the in vivo safety of NVs, and their potential role in obesity treatment. The outcome of this investigation involves the development of futuristic combinatorial nanovesicles that integrate gene silencing and metabolic regulatory systems to restore metabolic health.