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Vol. 19 (2027)

Biomimetic PD-1-Functionalized Immunostimulatory Nanomedicine Enables STING Activation and Durable Antitumor Immunity in Hepatocellular Carcinoma

https://doi.org/10.1007/s40820-026-02320-7
Yanbing Cao
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Xinyi Lin
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Bingchen Wu
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Yang Li
State Key Laboratory of Structural Chemistry & CAS Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, People’s Republic of China
Wenrui Zhu
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Binxin Liu
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Aixian Zheng
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Lingjie Wu
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Yanyang Wang
Department of Radiation Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, People’s Republic of China
Xiaolong Liu
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China
Ming Wu
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China

Corresponding Author: Ming Wu

wmmj0419@163.com

Nano-Micro Letters, Vol. 19 (2027), Article Number: 9

Abstract

Hepatocellular carcinoma (HCC) responds poorly to immune checkpoint blockade, largely because of an immunologically cold tumor microenvironment (TME) characterized by deficient antigen presentation and impaired cytotoxic T cell responses. Analysis of numerous HCC clinical cohorts, including our institutional datasets, reveals that stimulator of interferon genes (STING) pathway activity is positively correlated with patient survival, enhanced antigen presentation capacity, and an immune-activated TME. However, achieving effective and controllable STING activation in immune-cold HCC tumors remains challenging. Here, we develop a biomimetic nanomedicine that integrates photothermal therapy (PTT), STING pathway activation, and immune checkpoint blockade to treat refractory HCC. A coordination nanomedicine MCI-NP is engineered by co-encapsulating the STING agonist MSA-2 and indocyanine green (ICG) via Cu2+-mediated chelation, enabling stabilized PTT-induced immunogenic cell death together with robust STING-driven innate immune activation. Further cloaked with PD-1-overexpressing cell membranes, MCI-NP@mPD-1 achieves an approximately fivefold increase in tumor accumulation compared with uncoated MCI-NP and enables localized PD-1/PD-L1 axis blockade. Following a single treatment, MCI-NP@mPD-1-based photothermal immunotherapy effectively suppresses primary tumor growth and significantly prolongs survival by remodeling the TME toward an immune-active state, while inducing durable systemic immune memory that effectively limited postoperative lung metastasis. Without introducing additional nanocarriers or excipients, MCI-NP@mPD-1 offers a promising therapeutic paradigm for photothermal immunotherapy of immune-cold HCC.


Highlights:
1 Clinical cohort analyses identify stimulator of interferon genes (STING) signaling as a key determinant of immune responsiveness in hepatocellular carcinoma (HCC), providing a data-driven rationale for nanomedicine design.
2 A carrier-free coordination nanomedicine co-assembles MSA-2 and indocyanine green to couple photothermal-induced immunogenic cell death with STING activation, while PD-1 membrane camouflage enables ~fivefold tumor accumulation and localized checkpoint blockade.
3 This integrated strategy converts immune-cold HCC into an immune-active state, achieving durable tumor control and systemic immune memory against metastasis.

Keywords

Hepatocellular carcinoma STING agonist Photothermal therapy Biomimetic nanomedicine Immune checkpoint blockade
Cao, Yanbing, Xinyi Lin, Bingchen Wu, Yang Li, Wenrui Zhu, Binxin Liu, Aixian Zheng, Lingjie Wu, Yanyang Wang, Xiaolong Liu, and Ming Wu. 2026. “Biomimetic PD-1-Functionalized Immunostimulatory Nanomedicine Enables STING Activation and Durable Antitumor Immunity in Hepatocellular Carcinoma”. Nano-Micro Letters 19 (July):9. https://doi.org/10.1007/s40820-026-02320-7.
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