Cyclodextrin metal-organic frameworks (CD-MOF) as delivery carriers have gained great attention in the biomedical field. However, limited by challenges of moisture-sensitive nature, the design and application of CD-MOF-based hair follicle delivery for androgenic alopecia (AGA) has rarely been explored. We developed the metal-organic frameworks as hair follicle-targeted delivery system (SA-MOF), stearic acid (SA) was used to modify metal-organic frameworks to form a protective hydrophobic layer on the surface and provide the additional hair growth-promoting effect. Cardamonin (CAR), a newly discovered biosafety natural product, was encapsulated in SA-MOF (CAR@SA-MOF) to promote the therapeutic efficacy on AGA. CD-MOF surface-engineered nanoparticles modified by SA avoided the rapid hydration and disintegration of CD-MOF in water, which improved the drug release and follicular deposition of drug. Assisted by the delivery of SA-modified CD-MOF carriers, the drug significantly promoted cell proliferation and migration, achieving the promoting effect on hair follicle differentiation and hair regeneration in testosterone-challenged C57BL/6 mice. Simultaneously, SA modification provided additional promoting effects on human dermal papilla cell proliferation, regulating effect on keratinocyte growth factor, and activating effect of key signaling pathways. The surface engineering design of CD-MOF hair follicle drug delivery based on SA modification exhibits significant potential for the treatment of hair follicle and sebaceous gland-related diseases.