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

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.