Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD 21218.
Whiting School of Engineering, Institute for NanoBiotechnology, The Johns Hopkins University, Baltimore, MD 21218.
Proc Natl Acad Sci U S A. 2023 May 2;120(18):e2204621120. doi: 10.1073/pnas.2204621120. Epub 2023 Apr 25.
The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic "don't eat me" signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers an antitumor T cell response. As adjuvant therapy after surgery, this aCD47/PF supramolecular hydrogel effectively suppresses primary brain tumor recurrence and prolongs overall survivals with minimal off-target side effects.
脑内独特的与癌症相关的免疫抑制作用,加上浸润性 T 细胞的缺乏,导致胶质母细胞瘤(GBM)患者接受基于 T 细胞的免疫疗法的反应率低和治疗效果差。在这里,我们报告了一种自组装的紫杉醇(PTX)纤维(PF)水凝胶,它可刺激巨噬细胞介导的免疫反应,用于局部治疗复发性脑胶质瘤。我们的结果表明,含有 aCD47 的水 PF 溶液可直接沉积到肿瘤切除腔中,从而能够无缝地填充腔并长时间释放两种治疗药物。PTX PF 可引发免疫刺激的肿瘤微环境(TME),从而使肿瘤对 aCD47 介导的阻断抗吞噬“别吃我”信号敏感,进而促进巨噬细胞吞噬肿瘤细胞,并引发抗肿瘤 T 细胞反应。作为手术后的辅助治疗,这种 aCD47/PF 超分子水凝胶可有效抑制原发性脑肿瘤复发,并延长总生存期,且副作用极小。
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