Materializing RAFT‐Made Self‐Immolative Poly(Disulfide)s From α‐Lipoic Acid: Fabrication of Microneedle‐Enabled Biodegradable Nanomedicine for Anti‐Melanoma Therapy

ABSTRACT The advent of copolymerization techniques involving α‐lipoic acid (LA) and vinyl monomers has significantly transformed the synthetic paradigms of self‐immolative poly(disulfide)s. Further leveraging their structure–function–property–design interplay and eventually creating advanced materials are highly appreciated yet remains largely unexplored. A key advancement of this study lies in bridging the divide between controlled LA/vinyl copolymerization and practical materials, by fabricating biodegradable anti‐melanoma nanomedicine derived from well‐defined self‐immolative poly(disulfide)s. To do so, reversible addition–fragmentation chain transfer (RAFT) copolymerization of LA and 2,6‐diaminopyridine‐substituted vinyl monomer (DAP) is first conducted, endowing glutathione (GSH)‐degradable amphiphilic poly(disulfide)s vehicles, P(DAP‐ co ‐LANa), equipping hetero‐complementary H‐bonding DAP motifs toward the chemotherapeutic fluorouracil‐1‐acetic acid (FUA). On the other hand, FUA is tethered onto the photothermal agent IR780 to afford multifunctional prodrug FUA780, incorporating an H‐bonding array, chemotherapeutic, and photothermal activities. DAP/FUA H‐bonding interaction‐mediated assembly thus endow the construction of targeted smart nanomedicine FUA780@P(DAP‐ co ‐LANa). Moreover, to effectively cross the skin barrier, FUA780@P(DAP‐ co ‐LANa) is embedded within dissolvable microneedles, indeed standing out in malignant melanoma treatment, via spatiotemporal cargo delivery and synergistic chemo/photothermal therapy (CT/PTT). Such a controlled synthetic approach and well‐defined structural characteristics through LA/vinyl copolymerization are anticipated to serve as a pivotal foundation for advancing the design principles underlying dynamic material paradigms.