Skin photoaging caused by chronic UV radiation usually leads to extracellular matrix (ECM) degradation and a persistent pro-inflammatory microenvironment. Although lipid nanoparticles (LNPs) have been reported to deliver collagen mRNA to treat photoaged skin, their clinical translation remains severely limited due to lipid-induced inflammation and other side effects. To overcome this limitation, we developed a biomimetic platelet-derived nanovesicle (PNV)-lipid nanoparticle hybrid (PLH) to deliver collagen III mRNA (COL3A1) for skin rejuvenation. This hybrid loaded with COL3A1 (C3-PLH) was found to have enhanced uptake by damaged fibroblasts through surface-displayed CD62P protein. In vivo delivery tests showed that C3-PLH show a 3.1-fold higher skin retention and extend protein expression to 36 h without leaking into the liver. In a UVB-induced photoaging mouse model, C3-PLH treatment drove robust in situ collagen expression and achieved a remarkable 86.5% reduction in wrinkle area on day 21, compared to only a 25.8% reduction for conventional C3-LNP. Importantly, C3-PLH actively cleared harmful reactive oxygen species (ROS), reduced inflammation by promoting M2 macrophage polarization, and enhanced blood vessel growth. This synergistic dual-action strategy activated the TGF-β1/Smad-3 pathway while blocking the collagen-destroying enzyme MMP-9, successfully rebuilding a youth-associated skin architecture by lowering the dermal COL1A1/COL3A1 ratio to 2.2. Consequently, this platelet-derived nanovesicle/LNP hybrid offers a highly effective, safe, and microenvironment-reprogramming biomimetic strategy for advanced skin rejuvenation.
