Biomimetic Dual-Driven Janus Nanorobots for Enhanced Penetration and Combined Gas/Photothermal/Photodynamic/Catalytic Therapy of Pancreatic Cancer

Abstract

Pancreatic cancer (PC) remains an extremely lethal malignancy due to its dense desmoplastic stroma and aberrant tumor microenvironment (TME), which severely impedes the efficacy of conventional therapies. Herein, a biomimetic dual-driven Janus nanorobot (rCeGLI@PM) is strategically constructed via the asymmetric decoration of l-arginine (l-Arg)-functionalized and indocyanine green (ICG)-loaded poly(amidoamine) dendrimers onto CeOx nanozymes, followed by homologous Panc02 cell membrane camouflage. The formed nanorobots exhibit precise tumor accumulation via homologous targeting and deep penetration through NIR-induced thermophoresis and gas generation propulsion. Within the TME, nanorobots initiate cascade catalysis that generates toxic hydroxyl radicals and depletes glutathione to exaggerate oxidative stress while replenishing oxygen to alleviate tumor hypoxia and amplify photodynamic therapy (PDT). Meanwhile, NIR-triggered photothermal therapy (PTT) accelerates the nanozymatic activity for enhanced catalytic therapy, and PDT-triggered NO forms peroxynitrite (ONOO–) to degrade the extracellular matrix. This establishes a self-amplifying feedback loop for enhanced intratumoral infiltration and overall therapeutic efficacy. Comprehensive evaluations in subcutaneous and orthotopic PC models confirmed that rCeGLI@PM achieved superior therapeutic outcomes through synergistic PTT/PDT/gas/catalytic therapy. In summary, the strategic asymmetrical decoration of multifunctional dendrimers on nanozymes establishes a facile and versatile paradigm for engineering self-propelled nanorobots capable of multimodal synergistic therapies.