PD-L1 vNAR promotes hair growth by modulating hair shaft elongation through activating the leptin-STAT3 signaling

Programmed death ligand 1 (PD-L1) antibodies have achieved significant success in cancer immunotherapy. However, their roles beyond tumor treatment are not fully understood. In this study, we developed a shark-derived variable new antigen receptor targeting PD-L1, named 3P17, and investigated its role in promoting hair growth in C57BL/6J mice. The intravenous administration of 3P17 increased the proliferation of hair matrix cells, promoted hair shaft elongation, and accelerated hair follicle entry into anagen phage. Moreover, transcriptomic analysis showed that 3P17 increased leptin expression in mouse dorsal skin. Intravenous leptin phenocopied the hair shaft-elongating effect of 3P17. In contrast, the leptin receptor antagonist Allo-aca abrogated 3P17-induced hair shaft elongation. PD-L1, leptin, and phosphorylated STAT3 were co-expressed in hair matrix cells, and both 3P17 and leptin increased STAT3 phosphorylation in mouse dorsal skin. 3P17 also increased the expression of the proliferation-associated genes cyclin D1 and c-Myc in hair follicles. These results collectively indicated that the involvement of leptin-STAT3 signaling in the hair-growth-promoting effect of 3P17. To enhance drug delivery efficiency and patient compliance, we further evaluated the transdermal delivery of leptin using hollow sponge Haliclona sp. spicules (oSHS). oSHS-mediated delivery increased the proportion of leptin penetrating the skin to 43.69 ± 3.66% of the applied dose, representing a 3.28 ± 0.26-fold increase compared with leptin alone. Consistent with this enhanced uptake, oSHS increased leptin deposition into the viable epidermis and dermis, compared with microneedling and SHS, and promoted hair shaft elongation and hair growth in a mouse model of androgenetic alopecia. We propose oSHS-mediated transdermal delivery of leptin as a promising strategy to stimulate hair growth.