Hybrid-Fused Extracellular Vesicles from M2 Macrophages and Keratinocytes Attenuate Ultraviolet B-Induced Skin Photoaging via the Interleukin-4 Receptor Alpha/Janus Kinase/Signal Transducer and Activator of Transcription 3-Mediated Pathway

Abstract Chronic ultraviolet B (UVB) irradiation represents a primary environmental trigger of skin photoaging, a process defined by disrupted cutaneous redox balance, sustained low-grade inflammation, progressive cellular senescence, and impaired dermal collagen homeostasis. Among the underlying pathogenic events, aberrant macrophage polarization, progressive dermal cell senescence, and persistent collagen breakdown act as central drivers of photoaging deterioration. Traditional extracellular vesicles (EVs) derived from a single cell source carry a restricted repertoire of bioactive cargos, and thus fail to concurrently address the multiple interconnected pathological pathways that characterize photoaged skin. In this work, we generated hybrid fused extracellular vesicles (M2–KC–fEV) by combining vesicles from M2 macrophages and epidermal keratinocytes, and systematically assessed their protective efficacy against UVB-induced skin photodamage along with the underlying molecular regulatory mechanisms. Multidimensional characterization verified that M2–KC–fEV displayed a homogeneous size distribution, typical bilayer vesicular morphology, and stable surface zeta potential, and were readily internalized by skin derived cells. In UVB-injured mouse keratinocytes and dermal fibroblasts, treatment with M2–KC–fEV markedly reduced DNA double-strand breaks, suppressed excess reactive oxygen species production, and lowered proinflammatory cytokine secretion. The vesicles also alleviated cellular senescence and restored the proliferative and migratory abilities of damaged skin cells. In addition, the hybrid vesicle preparation modulated macrophage polarization states, inhibiting the proinflammatory M1 phenotype while shifting cells toward the anti-inflammatory, tissue reparative M2 phenotype. In line with in vitro observations, prophylactic subcutaneous administration of M2–KC–fEV in UVB-challenged SKH-1 hairless mice visibly reduced skin wrinkling and roughness, normalized epidermal thickness, enhanced type I collagen deposition, and inhibited MMP-3-driven collagen degradation. Mechanistic analyses revealed that the polarization-regulating effect of M2–KC–fEV is associated with the IL-4Rα/JAK/STAT3 signaling axis. Activation of this axis contributes to dampening inflammatory cascade amplification, alleviating oxidative damage and senescence accumulation, and ultimately ameliorating UVB-induced cutaneous photoaging. Collectively, M2–KC–fEV integrate anti-inflammatory, epidermal-protective, and dermal matrix-modulating activities, delivering enhanced combinatorial benefits against UVB-induced skin injury. Our findings support the potential of this cell-free nanotherapeutic platform for the prevention and mitigation of skin photoaging.