Macrophage-derived Extracellular Vesicles Disguised AIEgen/IDO1 Inhibitor Nanoplatform Reactivate “Immune-Hot” for Photothermal Immunotherapy via Multi-Dimensionally Reprograms Tumor Microenvironment

Abstract

Reversing the tumor microenvironment (TME) from “cold” to “hot” tumor represents a pivotal strategy to overcome the clinical bottleneck of poor response rates to immunotherapy in solid tumors. Herein, we innovatively employed a macrophage bioreactor to induce M0 macrophage polarization and the secretion of functional extracellular vesicles (M1-EVs) through co-incubation with hollow mesoporous silica nanoparticles loaded with the aggregation-induced emission photothermal agent AXCB6 and the IDO1 inhibitor NLG919. Notably, this in-situ bioengineering approach preserves the inherent biological properties and activity stability of functional agents’ components. Upon near-infrared irradiation, AXCB6 induces direct tumor cell death via photothermal therapy (PTT) and elicits immunogenic cell death, which subsequently triggers both in-situ vaccine responses and systemic immunity. Concomitantly, NLG919 inhibits the activity of PTT-driven IDO1 overexpression, reversing tryptophan metabolism-mediated immune suppression. Additionally, bioengineered M1-EVs with inherent repolarization capacity further reshape the inflammatory microenvironment and synergize with IDO1 blockade to potentiate immune activation. Through this cascaded amplification, the triple combination therapy exhibits superior therapeutic efficacy and favorable safety profiles compared to monotherapy and dual-drug combinations in both in vitro and in vivo. These findings indicate that the EV-integrated multi-dimensional system offers a promising strategy for converting “cold” tumors to “hot” tumors via Poseidon's “trident” mechanism: PTT-mediated physical ablation—repolarization-driven TME remodeling—immune checkpoint intervention.

Keywords

aggregation-induced emission (AIE) / engineered macrophage-derived extracellular vesicles / indoleamine 2,3-dioxygenase (IDO) inhibitor / repolarization / tumor microenvironment (TME)

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2025 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.