Androgenetic　alopecia　(AGA)　is　a　chronic　and　progressive　form　of　hair　loss　characterized　by　vascular　degeneration　in　the　perifollicular　microenvironment,　leading　to　cell　apoptosis　and　eventual　loss　of　hair　follicles　(HFs).　Traditional　therapeutic　formulations,　such　as　Minoxidil　(MXD)　tincture,　have　limitations　in　reshaping　the　perifollicular　microenvironment　and　exhibit　limited　effectiveness.　Here,　we　report　a　multi-synergistic　therapeutic　platform　for　high-performance　hair　regeneration　therapy.　The　platform　combines　microneedle　(MN)　patches　loaded　with　MXD-encapsulated　nanostructured　lipid　carriers　(MXD-NLC-MNs)　and　cold　atmospheric　plasma　(CAP).　The　MNs＇　mechanical　strength　enables　efficient　transdermal　delivery　of　MXD　to　the　targeted　dermal　papilla　cells,　promoting　cell　proliferation.　Furthermore,　in　collaboration　with　MXD,　the　mechanical　stimulation　exerted　by　MN　application　synergistically　upregulates　the　expression　of　vascular　endothelial　growth　factor,　leading　to　neoangiogenesis.　Meanwhile,　the　transient　microchannels　in　the　skin　created　by　MNs　facilitate　the　transdermal　delivery　of　CAP-generated　nitric　oxide　(NO)　to　the　sites　of　HF　lesions,　whereby　the　synergistic　interaction　between　MXD　and　NO　boosts　perifollicular　vasodilation.　Consequently,　the　perifollicular　microenvironment　can　be　effectively　reshaped　to　accelerate　hair　regeneration　in　AGA　murine　models.　This　multi-synergistic　combination　therapy　strategy　would　hold　great　promise　for　effectively　treating　AGA　and　promoting　hair　regrowth.