Jahn-Teller distortion-engineered self-propelled nanorobots for mitochondrial targeting and bioenergetic disruption in tumor therapy

Mitochondrial metabolism plays a pivotal role in tumor progression, yet effective therapeutic targeting remains constrained by limited tissue penetration and lack of spatiotemporal control. Herein, we present Jahn-Teller distortion-engineered, self-propelled nanorobots (IDP@Z@AP) that integrate catalytic oxygen generation, mitochondria-targeted drug delivery, and real-time 3D NIR-II photoacoustic (PA) imaging for precision tumor therapy. The nanorobots are fabricated by co-encapsulating a NIR-II photothermal agent (IR1048) and a mitochondria-targeting chemotherapeutic (DOX-TPP) within a ZIF-8 framework, followed by in situ anchoring of ultrasmall AuPt bimetallic nanozymes. Pt-induced Jahn-Teller distortion modulates the electronic structure of AuPt, enhancing glucose oxidase- and catalase-like activities. Under NIR-II laser irradiation, photothermal-enhanced cascade catalysis drives autonomous motion and catalyzes intratumoral O₂ generation, facilitating deep tumor infiltration. <i>In vitro</i> studies reveal efficient mitochondrial targeting, resulting in significant mitochondrial membrane depolarization, intracellular ATP depletion, and suppressed cell migration and invasion. <i>In vivo</i>, 3D NIR-II PA imaging enables noninvasive visualization of nanorobot biodistribution and real-time mapping of catalytic oxygen generation within tumor tissues. This nanorobotic platform effectively modulates tumor hypoxia and enhances chemotherapeutic delivery to mitochondria, ultimately achieving potent tumor suppression. The work offers a smart, catalytically driven, mitochondria-targeted strategy with real-time therapeutic feedback for subcellular-level cancer therapy.