Transdermal　drug　delivery　system　(TDDS)　offers　lower　systemic　toxicity　and　good　patient　compliance,　making　it　a　promising　treatment　option　for　skin-related　cancers.　However,　physiological　barriers　in　the　skin　frequently　impede　the　therapeutic　efficiency　of　TDDS.　To　address　this,　a　unique　self-assembled　TDDS　that　incorporates　disulfide　pendant　groups　(termed　Sup-TDDS)　is　presented.　It　is　formulated　with　dithiolane-containing　lipoic　acid　(LA),　photosensitizers　Ce6,　and　chemotherapeutic　agents　trametinib.　Pendant　disulfide　moieties　on　Sup-TDDS　facilitate　thiol-disulfide　exchange　reactions　with　exofacial　thiols　on　cell　surfaces,　thus　enhancing　stratum　corneum　penetration.　In　contrast　to　intravenous　injection,　topical　administration　of　Sup-TDDS　can　penetrate　deeper　into　the　skin　(＞　500　µm)　and　promote　drug　accumulation　in　subcutaneous　tumors.　In　a　B16F10-bearing　mouse　model,　Sup-TDDS　treatment　demonstrates　significant　anti-tumor　effects　in　primary　and　recurrent　melanoma,　benefiting　from　the　synergistic　effects　of　Ce6　and　trametinib.　These　results　underscore　that　Sup-TDDS＇s　transdermal　properties　allow　non-invasive　melanoma　therapy,　implying　the　potential　of　nanodrugs　containing　pendant　disulfides　for　transdermal　treatment　of　skin　illnesses.　©　2024　Wiley-VCH　GmbH.