Synergistic DNA repair inhibition and genotoxic therapy in cisplatin-resistant tumors via microneedle-based co-delivery of PROTAC and Pt(IV)

Cisplatin resistance in tumors is closely linked to the upregulation of the nucleotide excision repair (NER) pathway, particularly the excision repair cross-complementing-1–xeroderma pigmentosum complementation group F (ERCC1–XPF) complex. Here, we present a tumor-responsive microneedle (MN) patch platform for localized co-delivery of a NER-targeting proteolysis-targeting chimera (PROTAC) degrader (NERiP) and a Pt(IV) prodrug to overcome this resistance. This platform integrates pH-responsive PEG-PAE micelles, which co-encapsulate NERiP and Pt(IV), into dissolvable methacrylated hyaluronic acid microneedles for transdermal administration. Upon insertion into tumor-bearing skin, the MNs enable sustained and localized release of the micelles. In the mildly acidic tumor microenvironment, the micelles undergo surface charge reversal and rapid disassembly, resulting in synchronized release of both agents. This spatiotemporally coordinated delivery effectively downregulates ERCC1–XPF proteins and promotes platinum-induced DNA crosslinking, thereby enhancing apoptosis in cisplatin-resistant A375/CDDP melanoma cells. In vivo studies demonstrate that MN-mediated delivery significantly improves intratumoral drug accumulation and deep tissue penetration, achieving a tumor growth inhibition rate of 79.9% with minimal systemic toxicity. By combining tumor microenvironment-responsive release with minimally invasive localized delivery, this strategy enables synergistic NER pathway suppression and platinum-mediated genotoxicity. Furthermore, the MN platform ensures deep intratumoral distribution and prolonged retention, offering a promising therapeutic approach to address platinum resistance in solid tumors.