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

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.