Abstract

The development of next-generation nanotheranostics is increasingly challenged by the dual imperatives of environmental sustainability and the urgent need to overcome complex biological barriers, particularly multidrug resistance (MDR) in hepatocellular carcinoma (HCC). Herein, we bridge the gap between circular economy principles and precision nanomedicine by upcycling discarded eggshell membranes (ESM) into a hierarchical metabolic therapeutic platform. Utilizing the protein fiber network of ESM as a natural biotemplate, we orchestrated the anisotropic growth of calcium carbonate (CaCO3) into unique yolk–shell nanostructures (YSNs) via interfacial molecular recognition. This bioinspired architecture features a high specific surface area, enabling the efficient coloading of the chemotherapeutic cisplatin (CDDP) and ultrathin vanadium carbide (V4C3) MXene nanozymes, stabilized by a biotinylated carboxymethyl chitosan (Biotin-CMCS) targeting shell. Mechanistically, this “Trojan Horse” system exploits the acidic tumor microenvironment (TME) to trigger a rapid cascade of disassembly, releasing a surge of Ca2+ ions and MXene-driven reactive oxygen species (ROS). Crucially, we demonstrate that the resulting mitochondrial calcium overload instigates a catastrophic “bioenergetic crisis,” characterized by the irreversible opening of mitochondrial permeability transition pores (mPTP) and the precipitous depletion of intracellular adenosine triphosphate (ATP). This metabolic collapse effectively deactivates ATP-dependent DNA repair machineries (e.g.,poly(ADP-ribose) polymerase 1 (PARP1) and excision repair cross-complementation group 1 (ERCC1)), thereby reversing cisplatin resistance and sensitizing tumor cells to DNA damage. In vivo evaluations in HCC xenografts confirm potent tumor regression with minimal systemic toxicity, facilitated by the renal clearance of biodegradable