Cascade-driven β-Lapachone cycle in a photothermal/self-oxygenating MXene nanoplatform for synergistic tumor therapy

The high heterogeneity of malignant tumors and inherent limitations of conventional monotherapies have propelled multimodal synergistic treatments to the forefront of current research. Photothermal therapy (PTT) has garnered significant attention due to its non-invasive nature and favorable safety profile; however, its therapeutic efficacy is often constrained by the limited tissue penetration depth of near-infrared (NIR) light and insufficient targeting capabilities. In recent years, enzyme-based catalytic therapies have emerged as a highly promising strategy for tumor intervention. Two-dimensional transition metal carbides MXene (such as Ti₃C₂Tx) possess exceptional photothermal conversion efficiency and excellent aqueous dispersibility, making them ideal candidates for PTT. Furthermore, Ti₃C₂Tx exhibits intrinsic catalase (CAT)-like activity, catalyzing the decomposition of H₂O₂ into O₂ within the hypoxic tumor microenvironment, thereby offering a novel approach to alleviating tumor hypoxia. This study constructed a multifunctional nanocatalytic system, HA-Ti₃C₂Tx@LAP, comprising hyaluronic acid (HA)-coated β-lapachone (LAP). Transmission electron microscopy revealed uniformly dispersed ultrathin flake-like structures with an average hydrated particle size of 211.13 ± 3.36 nm. The system exhibited pronounced microenvironment responsiveness: Under acidic conditions, in the presence of overexpressed hyaluronidase, and upon NIR-induced hyperthermia, LAP release reached 88.48%. It achieved a photothermal conversion efficiency of 23.87% and significant CAT-like enzyme activity. Both in vitro and in vivo experiments have demonstrated that, under NIR, this material catalyzes the decomposition of endogenous H₂O₂ into O₂ within tumors, thereby effectively alleviating intratumoral hypoxia. Moreover, the cascade catalytic reaction between MXene and LAP generates abundant reactive oxygen species, which induce intracellular oxidative stress and subsequently trigger apoptosis. This mechanism acts in synergy with the thermal ablation effect of PTT, collectively achieving a potent antitumor outcome.