Dual activation of cuproptosis and excessive autophagy by copper-bismuth metal-organic frameworks-loaded detachable microneedles in oral leukoplakia.

Abstract

Oral leukoplakia (OLK), a prevalent precancerous lesion with considerable malignant transformation potential, remains a major clinical challenge due to the lack of effective and minimally invasive therapies. Here, we developed novel copper-bismuth metal-organic frameworks (CBM) and incorporated them into a bilayer detachable microneedle system (CBMMN) to achieve localized and sustained delivery. CBM markedly downregulated pyruvate dehydrogenase kinase 3 (PDK3), thereby orchestrating the cooperative activation of cuproptosis and excessive autophagy, which synergistically suppressed the viability of dysplastic oral keratinocytes. In vivo studies further demonstrated that CBMMNs effectively eliminated OLK with minimal systemic toxicity, underscoring their therapeutic efficacy and biosafety. By combining cuproptosis and excessive autophagy, CBMMNs establish a mechanistic foundation distinct from conventional approaches and offer a novel therapeutic approach for OLK management.