Nanoparticle co-delivery of microtubule inhibitors and cisplatin overcomes DNA repair-mediated resistance in head and neck cancer

Cisplatin remains a foundational chemotherapeutic for head and neck squamous cell carcinoma (HNSCC), but its effectiveness is often limited by intrinsic or acquired resistance driven largely by enhanced DNA interstrand crosslink (ICL) repair. Through a combined screen of ICL repair and cisplatin resistance modulators, our current study identifies a strong synergy between cisplatin and microtubule-targeting agents (MTAs), including taxanes and colchicine. MTAs suppress ICL repair and overcome cisplatin resistance in HNSCC cells. Mechanistically, MTAs impair the resolution of cisplatin-induced lesions, consistent with reduced recruitment of the ERCC1-XPF endonuclease required for ICL unhooking. MTAs also diminish homologous recombination, accompanied by reduced DNA damage recruitment of RPA32 and RAD51. Moreover, MTAs disrupt DNA damage checkpoint activation in response to cisplatin, permitting cell cycle transit through S-phase despite persistent DNA damage. Together, these effects drive enhanced DNA damage accumulation and apoptosis in HNSCC cells treated with the cisplatin-MTA combination. To further harness this synergy for therapeutic benefit, we employ poly(2-oxazoline)-based micelles to co-encapsulate paclitaxel and a hydrophobic cisplatin prodrug with two aliphatic hexane chains. This nanoformulation is developed to improve drug solubility and release profiles, resulting in optimized pharmacokinetics and enhanced tumor delivery and retention. Indeed, in a syngeneic HNSCC model, nanoparticle co-delivery of paclitaxel and cisplatin prodrug produced markedly superior antitumor efficacy compared to the free drug combination. Collectively, our findings define a mechanism-guided, nanoparticle-enabled therapeutic approach for sensitizing HNSCC to platinum-based chemotherapy through selective disruption of DNA damage responses.