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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\u2013F10 melanoma models, including 2D cultures, 3D spheroids, and in vivo tumors. Remarkably, treatment in an in vivo B16\u2013F10 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.<\/jats:p>","DOI":"10.1021\/jacs.6c05546","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:02:09Z","timestamp":1786438929000},"page":"42949-42968","source":"Crossref","is-referenced-by-count":0,"title":["Overcoming\nBarriers in Solid Tumors: Lactate-Fueled\nNanomotors Enhance Penetration and Reverse Immunosuppression"],"prefix":"10.1021","volume":"148","author":[{"given":"Juan Jose\u0301","family":"Esteve-Moreno","sequence":"first","affiliation":[{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Universitat de Vale\u0300ncia , , Cami\u0301 de Vera, s\/n ,","place":["Vale\u0300ncia, Spain, 46022"]},{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia , , C\/Eduardo Primo Yu\u0301fera, 3 , ,","place":["Vale\u0300ncia, Spain, 46012"]},{"name":"Instituto de Salud Carlos III , , ,","place":["Madrid, Spain, 28029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Escudero","sequence":"additional","affiliation":[{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Universitat de Vale\u0300ncia , , Cami\u0301 de Vera, s\/n ,","place":["Vale\u0300ncia, Spain, 46022"]},{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia , , C\/Eduardo Primo Yu\u0301fera, 3 , ,","place":["Vale\u0300ncia, Spain, 46012"]},{"name":"Instituto de Salud Carlos III , , ,","place":["Madrid, Spain, 28029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Hicke","sequence":"additional","affiliation":[{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Universitat de Vale\u0300ncia , , Cami\u0301 de Vera, s\/n ,","place":["Vale\u0300ncia, Spain, 46022"]},{"name":"Instituto de Salud Carlos III , , ,","place":["Madrid, Spain, 28029"]},{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Instituto de Investigacio\u0301n Sanitaria La Fe (IIS La Fe) , , Avenida Fernando Abril Martorell 106, Torre A , ,","place":["Vale\u0300ncia, Spain, 46026"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vi\u0301ctor","family":"Sanz-A\u0301lvarez","sequence":"additional","affiliation":[{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Universitat de Vale\u0300ncia , , Cami\u0301 de Vera, s\/n ,","place":["Vale\u0300ncia, Spain, 46022"]},{"name":"Instituto de Salud Carlos III , , ,","place":["Madrid, Spain, 28029"]},{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Instituto de Investigacio\u0301n Sanitaria La Fe (IIS La Fe) , , Avenida Fernando Abril Martorell 106, Torre A , ,","place":["Vale\u0300ncia, Spain, 46026"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u0301a","family":"Miralles-Buleo","sequence":"additional","affiliation":[{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Universitat de Vale\u0300ncia , , Cami\u0301 de Vera, s\/n ,","place":["Vale\u0300ncia, Spain, 46022"]},{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia , , C\/Eduardo Primo Yu\u0301fera, 3 , ,","place":["Vale\u0300ncia, Spain, 46012"]},{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Instituto de Investigacio\u0301n Sanitaria La Fe (IIS La Fe) , , Avenida Fernando Abril Martorell 106, Torre A , ,","place":["Vale\u0300ncia, Spain, 46026"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7079-8589","authenticated-orcid":true,"given":"Mari\u0301a Dolores","family":"Marcos","sequence":"additional","affiliation":[{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia, Universitat de Vale\u0300ncia , , Cami\u0301 de Vera, s\/n ,","place":["Vale\u0300ncia, Spain, 46022"]},{"name":"Instituto de Salud Carlos III , , ,","place":["Madrid, Spain, 28029"]},{"name":"Universitat Polite\u0300cnica de Vale\u0300ncia , , Cami\u0301 de Vera s\/n ,","place":["Vale\u0300ncia, Spain, 46022"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-4413","authenticated-orcid":true,"given":"M. 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