Intradermal delivery of N1-methylpseudouridine-modified BCL-2 mRNA as a programmable gene therapy to reverse UVB-induced skin photoaging

Background Photoaging, driven by ultraviolet-B (UVB)–induced oxidative and inflammatory cascades, accelerates extracellular-matrix degradation and remains difficult to reverse with current small-molecule, topical, or device-based approaches. Network-based bioinformatics analyses implicate BCL-2 at the intersection of PI3K–AKT and IL-6/NF-κB-driven pyroptotic signaling, suggesting that transient, locally confined augmentation of BCL-2 could decouple inflammatory cell death from extracellular-matrix homeostasis in photoaged skin. Technology Leveraging nucleic-acid and chemical base modification, we engineered an intradermally deliverable, N1-methylpseudouridine-stabilised modified BCL-2 mRNA (modBCL-2) platform designed to achieve high-efficiency, transient BCL-2 expression in primary human dermal fibroblasts (HDFs) and murine skin. The core principle is a single-component, non-viral gene therapy that suppresses IL-6/NF-κB-mediated pyroptosis while preserving collagen synthesis, using minimally invasive micro-bolus injections without genomic integration. Building on our previous modRNA-based regenerative work, we implemented a tiered translational workflow that couples in-silico target discovery with in-vitro, cellular, and in-vivo validation in UVB-induced photoaging models. Results High-throughput microfluidic transfection delivered >90 % GFP-modRNA into primary HDFs and sustained an approximately 8-fold up-regulation of BCL-2 from 24 h to 72 h. In UVB-irradiated HDFs, BCL-2-modRNA could reduce early + late apoptosis, reversed G0/G1 arrest with recovery of proliferative index, suppressed inflammation- and pyroptosis-related gene/protein expression, increased collagen synthesis- and decreased collagen degradation-associated gene/protein expression. In a barcode-randomised, placebo-controlled nude-mouse photoaging model, intradermal BCL-2-modRNA micro-boluses over 28 days reduced wrinkle number and wrinkle area, restored skin thinning, and countered collagen loss, and downregulated the expression of key proteins in the IL-6/NF-κB signaling pathway and those involved in pyroptosis. Collectively, in-silico network pharmacology, high-throughput microfluidic transfection, and barcode-randomised delivery were used to validate BCL-2 modRNA as a locally controllable, highly transfectable chassis for dermato-therapeutics. Our findings establish BCL-2 modRNA as a promising, programmable therapeutic modality for skin photoaging. By simultaneously inhibiting cell pyroptosis and inflammation, this strategy offers a multifaceted approach to reversing UVB-induced skin damage, with potential for clinical translation in regenerative dermatology.