Ascorbic palmitate (AP) is widely used in the topical pharmaceutical or cosmetic formulations for melasma treatment. However, the presence of the skin barriers makes it difficult for the highly lipophilic drug molecules to traverse the stratum corneum (SC) and diffuse into the viable epidermis (EP) to reach the melanocytes, thereby exerting suboptimal antimelasma effects. Herein, AP was encapsulated into the transfersomes (TFs), yielding AP-TFs. AP-TFs utilized the deformability of TFs to squeeze through the skin pores in the SC under the transepidermal hydration gradient forces, leading to 14.1-fold increase in AP accumulation to the EP. AP-TFs could slowly release the encapsulated AP, while whether the released AP or transfersomal AP showed comparable uptake into the melanocytes, thereby exerting similar inhibitory effects on tyrosinase activity and melanogenesis. Ultimately, in the rat melasma model, AP-TFs showed superior antimelasma efficacy to free AP, with effective relief of oxidative stress and inflammation in the skin. Moreover, AP-TFs did not induce skin irritation. Therefore, the study provides a safe and effective approach to elevating the delivery of highly lipophilic drugs to the EP for enhanced treatment of melasma.

抗坏血酸棕榈酸酯 (AP) 广泛用于治疗黄褐斑的局部药物或化妆品配方。然而，皮肤屏障的存在使得高度亲脂性的药物分子难以穿过角质层 (SC) 并扩散到有活力的表皮 (EP) 中以到达黑素细胞，从而发挥次优的抗粘液作用。在此，AP被封装到传递体（TFs）中，产生AP-TFs。AP-TFs 利用 TFs 的变形能力在经表皮水化梯度力下挤过 SC 中的皮肤毛孔，导致 AP 向 EP 的积累增加了 14.1 倍。AP-TFs 可以缓慢释放封装的 AP，而释放的 AP 或转移体 AP 是否显示出可比的吸收到黑素细胞中，从而对酪氨酸酶活性和黑色素生成发挥类似的抑制作用。最终，在大鼠黄褐斑模型中，AP-TF 显示出优于游离 AP 的抗黑斑功效，可有效缓解皮肤中的氧化应激和炎症。此外，AP-TFs 不会引起皮肤刺激。因此，该研究提供了一种安全有效的方法来提高高度亲脂性药物向 EP 的递送，以加强黄褐斑的治疗。