MXene-Engineered MgB ₂ Nanoprodrugs with Acid-Responsive Hydrogen Evolution for Cooperative Photothermal Cancer Ablation

Conventional photothermal therapy (PTT) offers localized tumor ablation, yet its clinical impact is curtailed by heat shock protein (HSP)-mediated thermotolerance. Here, we introduce a conceptually new strategy that couples hydrogen gas therapy with PTT to overcome this intrinsic limitation. We engineered a multifunctional nanosystem, which was constructed from two-dimensional Ti₃C₂T_<i>x</i> nanosheets loaded with acid-responsive MgB₂ prodrugs and further stabilized by polyethylene glycol, termed as MgB₂-Ti₃C₂T_<i>x</i>@PEG. This nanosystem can hydrolyze to produce hydrogen gas and accelerate the reaction in a slightly acidic tumor microenvironment. Excited with an 808 nm laser, MgB₂-Ti₃C₂T_<i>x</i>@PEG achieves a high photothermal conversion efficiency of 31.06%, while the generated heat can also simultaneously accelerate the hydrogen gas release. The liberated hydrogen gas then orchestrates a cascade of therapeutic effects; it triggers oxidative stress and a surge in reactive oxygen species within cancer cells, thus disrupting mitochondrial respiration function. Concurrently, the expression of HSPs is down-regulated, thereby eliminating thermotolerance and sensitizing tumor cells to PTT. This synergistic interplay ultimately results in robust tumor growth inhibition. Moreover, the strong near-infrared absorption and photoacoustic properties of Ti₃C₂T_<i>x</i> enable real-time imaging guidance, integrating therapy and diagnostics into a single nanoplatform. This work pioneers the use of hydrogen molecules to dismantle cellular defense mechanisms against hyperthermia, offering a paradigm shift toward more precise, potent, and intelligently guided PTT.