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

Abstract

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.