Engineering exosome membrane disguised thermal responsive system for targeted drug delivery and controlled release across the blood-brain barrier

Zhe Han; Haina Huang; Boyan Li; RongRong Zhao; Qingtong Wang; Hong Liu; Hao Xue; Weijia Zhou; Gang Li

doi:10.1016/j.mtbio.2025.101656

Engineering exosome membrane disguised thermal responsive system for targeted drug delivery and controlled release across the blood-brain barrier

Mater Today Bio. 2025 Mar 11:32:101656. doi: 10.1016/j.mtbio.2025.101656. eCollection 2025 Jun.

Authors

Zhe Han^{1

2

3}, Haina Huang⁴, Boyan Li^{1

2

3}, RongRong Zhao^{1

2

3}, Qingtong Wang^{1

2

3}, Hong Liu^{4

5}, Hao Xue^{1

2

3}, Weijia Zhou⁴, Gang Li^{1

2

3}

Affiliations

¹ Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, 250012, China.
² Institute of Brain and Brain-Inspired Science, Ji'nan, Shandong, 250012, China.
³ Shandong Key Laboratory of Brain Function Remodeling, Ji'nan, Shandong, 250012, China.
⁴ Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Ji'nan, 250022, China.
⁵ State Key Laboratory of Crystal Materials, Shandong University, Ji'nan, 250100, China.

Abstract

The blood-brain barrier (BBB) presents a significant challenge for the delivery of chemotherapy drugs to brain tumors, leading to ineffective drug concentrations at the tumor site and contributing to chemotherapy resistance. The hypoxic tumor microenvironment further complicates this process, ultimately resulting in poor patient prognosis. In this study, we developed a thermoresponsive nanocarrier system that incorporates (Ru)(Pt) bimetallic nanoparticles onto defective TiOx nanoparticles with abundant oxygen vacancies, generating composite Ru/Pt-TiOx nanoparticles with photothermal and photocatalytic properties. The Ru and Pt in the nanoparticles enhance the metal-carrier interactions, with Ru increasing both light absorption and photothermal conversion efficiency and Pt catalyzing the conversion of endogenous H₂O₂ in tumors to produce oxygen. The oxygen produced within the tumor microenvironment reduces HIF-1α, MDR1 and P-gp expression, thereby inhibiting efflux and allowing doxorubicin to accumulate inside the cells. DOX was incorporated into a phase change material and combined with multiple Ru/Pt-TiOx nanoparticles to form composite RPTiOx-DOX particles that can control the release of DOX under near-infrared irradiation. In an effort to overcome the blocking effect of the BBB, we wrapped the RPTiOx-DOX nanoparticles with Angiopep-2-functionalized macrophage exosome membranes. Furthermore, the changes in the internal environment promote macrophage phenotypic transformation (M2→M1) to some extent and further inhibit tumor growth via immunoregulation. In this work, a novel drug delivery system capable of traversing the BBB and exerting synergistic antitumor effects through photostimulated therapeutic agents is described, providing innovative insights for the development of stimulus-responsive composite nanoparticle drug formulations.

Keywords: Exosome membrane camouflage; Glioblastoma; Multimodal synergistic therapy; Penetrating the blood‒brain barrier; Thermoresponsive nanocarrier system.