Advances in metal-organic framework-based drug delivery system in cuproptosis-mediated cancer therapy

Cancer continues to pose an immense burden on global health, ranking among the foremost causes of disease-associated mortality. Conventional diagnostic platforms for tumor biomarkers, while widely adopted, remain constrained by limited sensitivity, protracted workflows, and substantial economic costs, thereby restricting their clinical applicability. Therapeutic modalities such as chemotherapy and radiotherapy further compound the challenge, offering only modest selectivity and being accompanied by significant systemic toxicity and a high likelihood of relapse. Metal-organic frameworks (MOFs) represent a class of structurally tailorable nanomaterials composed of modular building units, featuring tunable porosity and favourable biocompatibility, which together provide an efficient platform for drug encapsulation and controlled release. Their tumour accumulation behaviour is strongly governed by key physicochemical parameters, including particle size, morphology, and surface chemistry. Pristine MOFs primarily rely on passive tumour targeting through the enhanced permeability and retention effect, whereas surface functionalization with targeting ligands can markedly improve tumor selective enrichment and cellular uptake. Consequently, the therapeutic delivery performance of MOFs must be critically assessed in relation to their specific structural design and surface engineering strategies. In parallel, the identification of cuproptosis, a mitochondria-centered copper-dependent mode of regulated cell death, has opened a distinct mechanistic avenue for oncological intervention. This process arises from the aberrant interaction of copper ions with lipoylated tricarboxylic acid cycle proteins, culminating in excessive protein acylation, destabilization of Fe-S cluster enzymes, proteotoxic stress, and mitochondrial collapse. The rapid evolution of pharmacological agents exploiting this pathway underscores its transformative therapeutic potential. This review critically consolidates recent progress at the interface of MOFs and cuproptosis, emphasizing design strategies, mechanistic insights, and therapeutic deployment, while also addressing unresolved issues in pharmacokinetics, biosafety, and translational feasibility that must be overcome for clinical realization.