Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy

Haifen Luo, Jingqi Lv, Peiye Wen, Shan Zhang, Wen Ma () and Zhen Yang ()
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Haifen Luo: Fujian Normal University
Jingqi Lv: Fujian Normal University
Peiye Wen: Fujian Normal University
Shan Zhang: Fujian Normal University
Wen Ma: Fujian Normal University
Zhen Yang: Fujian Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Despite the tremendous therapeutic promise of activating stimulators of interferon genes (STING) enable to prime robust de novo T-cell responses, biomechanics-mediated immune inhibitory pathways hinder the cytotoxicity of T cells against tumor cells. Blocking cancer cell biomechanics-mediated evasion provides a feasible strategy for augmenting STING activation-mediated anti-tumor therapeutic efficacy. Here, we fabricate a redox-responsive Methyl-β-cyclodextrin (MeβCD)-based supramolecular polyrotaxanes (MSPs), where the amphiphilic diselenide-bridged axle polymer loads MeβCD by the host-guest interaction and end-caping with two near-infrared (NIR) fluorescence probes IR783. The MSPs self-assemble with STING agonists diABZIs into nanoparticles (RDPNs@diABZIs), which enable simultaneous release of MeβCD and diABZIs in the redox tumor microenvironment. After the released diABZIs activate STING on antigen-presenting cells (APCs), de novo T-cell responses are initiated. Meanwhile, the released MeβCD depletes membrane cholesterol to overcome cancer-cell mechanical softness, which enhances the CTL-mediated killing of cancer cells. In the female tumor-bearing mouse model, we demonstrate that RDPNs@diABZIs lead to effective tumor regression and generate long-term immunological memory. Furthermore, RDPNs@diABZIs can achieve significant tumor eradication, with these mice remaining survival for at least 2 months.

Date: 2025
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DOI: 10.1038/s41467-025-57718-5

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