Hybrid Cell Membrane‐Coated NIR‐Photodegradable Carbon Nitride Nanozymes for Mangiferin Dual‐Targeted Delivery and Gas Mild Photothermal Immunotherapy Against Liver Fibrosis via the HIF‐1α/HSP27 Axis

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ABSTRACT Hypoxia, a hallmark pathological feature of liver fibrosis, upregulates HIF‐1α expression to drive hepatic stellate cell (HSC) activation, resulting in fibrotic lesions. Targeting activated HSCs (aHSCs) and achieving efficient liver fibrosis treatment remain daunting challenges. For the first time, we constructed a biomimetic carbon nitride‐based drug–gas codelivery platform HMCCNs@MAN for precise mild photothermal immunotherapy (< 45°C) for liver fibrosis. Specifically, by utilizing the immunocamouflage and fibrosis‐targeting properties of macrophage (MΦ) membranes, along with the homologous targeting ability of aHSCs membranes, the hybrid MΦ‐aHSC membrane‐coated, carbon dot‐doped carbon nitride (HMCCNs) achieved a dual‐targeted delivery of mangiferin (MAN) to liver fibrosis lesions. At the lesion site, HMCCNs enabled NIR‐triggered water splitting to produce oxygen and exhibited catalase‐like enzymatic activity, synergistically ameliorating hypoxic conditions. Simultaneously, HMCCNs demonstrated a high photothermal conversion efficiency of 69.52%. Furthermore, the photocorrosive effect endowed HMCCNs@MAN with significant NIR‐responsive drug release capability. Released MAN and generated oxygen cooperatively modulated the HIF‐1α/HSP27 axis, leading to an increased sensitivity of fibrotic lesions to thermotherapy. Notably, HMCCNs@MAN + NIR activated natural killer cells, thereby enhancing the immune response against aHSCs. This study reveals the great potential of HMCCNs@MAN as a mild photothermal‐immunotherapy strategy for liver fibrosis treatment.

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