A self-powered chloroplast-driven nanophotosystem for treating skin photoaging through rejuvenating mitochondria and revitalizing senescent fibroblasts

Skin aging is an inevitable biological process caused by cellular senescence and overexposure to harmful environmental factors such as ultraviolet (UV) radiation. Senescent fibroblasts with proliferation arrest, mitochondrial dysfunction and nicotinamide adenine dinucleotide phosphate (NADPH) depletion have been proposed as a major mechanism driving skin photoaging, but the specific therapies are currently lacking. Inspired by the self-powering potential of plant-derived photosynthetic system, we herein fabricated a novel nanophotosynthetic platform that integrated Chlorella-derived nanothylakoid units (NTUs) with hyaluronic acid (HA)-based microneedles (MNs) to specifically target senescent fibroblasts for treating skin photoaging. By equipped with photosynthesis (PS)-I/II and quinolinate phosphoribosyltransferase (QPRT), the NTU-MN photosystem remarkably increased mitochondrial biogenesis and adenosine triphosphate (ATP) generation, resumed NAD(P)H pool and increased cellular anabolism, addressing the heighted bioenergetic and biosynthetic requirement for highly turnover of fibroblasts during photoaging. Furthermore, with skin penetrating ability of MNs and camouflaging of fibroblast membranes, topical application of the nanophotosystem facilitated the intradermal release of NTUs, leading to regeneration of damaged tissues, increased collagen synthesis, decreased senescence-associated secretory phenotype (SASP), and hence alleviated photoaging of skin. Thus, we developed a "green nanoplatform" with significantly anti-aging efficacy, biocompatibility, and biosafety, opening new avenues for light-driven therapies for degenerative diseases.