Overcoming Barriers in Solid Tumors: Lactate-Fueled Nanomotors Enhance Penetration and Reverse Immunosuppression

Solid tumors present a therapeutic challenge due to their dense extracellular matrix and metabolically immunosuppressive microenvironment, which limit drug penetration and immune clearance. To overcome these barriers, we describe an engineered lactate-powered Janus nanomotor (NM(dox)-LOx) composed of a platinum (Pt) nanodendrite and a mesoporous silica nanoparticle (MSN), loaded with doxorubicin (Dox) and functionalized with the enzyme lactate oxidase (LOx). In this design, LOx acts as a protease-sensitive molecular gate for controlled Dox release and catalyzes the oxidation of tumor-accumulated lactate, using this metabolite as a biofuel to generate hydrogen peroxide, which is catalyzed by Pt into oxygen and water. This cascade generates a self-propulsive force that drives the nanomotor. Concurrently, catalytic lactate depletion reprograms the tumor microenvironment, promoting cytotoxic T cell infiltration and restoring immune activity. NM(dox)-LOx demonstrates efficient tumor accumulation and potent antitumor activity in human SK-MEL-103 and murine B16-F10 melanoma models, including 2D cultures, 3D spheroids, and in vivo tumors. Remarkably, treatment in an in vivo B16-F10 melanoma model achieved pronounced tumor regression and enhanced cytotoxic T cell infiltration, while maintaining minimal systemic toxicity. Overall, this multifunctional nanomotor couples enhanced drug delivery with immune activation, effectively overcoming the structural and metabolic barriers of solid tumors, and represents a promising strategy for self-propelled therapeutic nanoparticles in cancer treatment.