2. Academic Validation
  3. Spatiotemporal Sequential Delivery of Chidamide Regulates Macrophage Reprogramming in Lymphoma Microenvironment Through HDACs-STAT3 Pathway

Spatiotemporal Sequential Delivery of Chidamide Regulates Macrophage Reprogramming in Lymphoma Microenvironment Through HDACs-STAT3 Pathway

  • Adv Sci (Weinh). 2026 Mar 31:e02791. doi: 10.1002/advs.202502791.
Bo Dai 1 2,  Shuo Wang 3,  Xiaotong Peng 4,  Kunpeng Wu 1 2,  Mengyao Wu 1 2,  Zhaoning Lu 5,  Haoshu Zhong 1 2,  Xiaohan Qian 1 2,  Shuiyi Tan 1 2,  Hui Yang 1 2,  Tanlezi Sun 5,  Jing Wang 5,  Jie Zhang 5,  Hua Jiang 5,  Yin Tong 6,  Tong Chen 1 2
Affiliations

Affiliations

  • 1 Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.
  • 2 Center of Precision Medicine For Blood Diseases, Fudan University, Shanghai, China.
  • 3 Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 5 Obstetrics, and Gynecology Hospital, Fudan University, Shanghai, China.
  • 6 Department of Hematology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
PMID: 41915859 DOI: 10.1002/advs.202502791
Abstract

Tumor-associated macrophage (TAM) is an important component of immunosuppressive microenvironment, which has been indicated as a key contributor in the relapse of diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanism and the potential intervention regulating DLBCL-TAMs remains undefined. Here, we found that histone deacetylases (HDACs)-induced STAT3 deacetylation was critical for the M2 macrophages accumulation in DLBCL. Considering the unignorable adverse effects of HDAC Inhibitor chidamide in DLBCL treatment, we developed a M2-targeted delivery system with peptide-modified extracellular vesicle (M2pep-EVs) to obtain optimized intra-tumour delivery of chidamide. In combined with pH-responsive hydrogel TSPBA/PVA, chidamide was loaded in M2pep-EVs, and was intelligently released as Chid@M2pep-EVs in situ in the acidic lymphoma microenvironment. By targeted delivery to M2 macrophages, chidamide sufficiently inhibited HDACs, enhanced STAT3 acetylation, reprogrammed M2 proportion into M1 phenotype, and ultimately suppressed lymphoma growth in vivo. With reduced dosage and adverse reactions, our Chid@M2pep-EVs system provides a new translational strategy for treating refractory/relapsed lymphoma.

Keywords

chidamide; engineered EVs; hydrogel; lymphoma; macrophage reprogramming.

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