Overcoming Barriers in Solid Tumors: Lactate-Fueled Nanomotors Enhance Penetration and Reverse Immunosuppression.
6 affiliations
- 1Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Camí de Vera, s/n46022València, Spain.
- 2Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Centro de Investigación Príncipe Felipe, Universitat Politècnica de València, C/Eduardo Primo Yúfera, 3, 46012València, Spain.
- 3CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, 28029Madrid, Spain.
- 4Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Avenida Fernando Abril Martorell 106, Torre A, 46026València, Spain.
- 5Departamento de Química, Universitat Politècnica de València, Camí de Vera s/n46022València, Spain.
- 6Departamento de Química-Física, Universitat de València, Burjassot, 46100, València, Spain.
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.
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BibTeX
@article{estevemoreno2026overcoming,
title = {{Overcoming Barriers in Solid Tumors: Lactate-Fueled Nanomotors Enhance Penetration and Reverse Immunosuppression.}},
author = {Juan José Esteve-Moreno and Andrea Escudero and Francisco J Hicke and Víctor Sanz-Álvarez and María Miralles-Buleo and María Dolores Marcos and M Carmen Martínez-Bisbal and Alba García-Fernández and Paula Díez and Ramón Martínez-Máñez},
journal = {Journal of the American Chemical Society},
year = {2026},
month = oct,
doi = {10.1021/jacs.6c05546},
url = {https://europepmc.org/article/MED/42913522},
note = {CC BY},
}
RIS
TY - JOUR
TI - Overcoming Barriers in Solid Tumors: Lactate-Fueled Nanomotors Enhance Penetration and Reverse Immunosuppression.
AU - Juan José Esteve-Moreno
AU - Andrea Escudero
AU - Francisco J Hicke
AU - Víctor Sanz-Álvarez
AU - María Miralles-Buleo
AU - María Dolores Marcos
AU - M Carmen Martínez-Bisbal
AU - Alba García-Fernández
AU - Paula Díez
AU - Ramón Martínez-Máñez
PY - 2026
DA - 2026/10/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c05546
UR - https://europepmc.org/article/MED/42913522
AB - 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.
SN - 0002-7863
SN - 1520-5126
ER -