尽管免疫疗法在治疗多种肿瘤方面取得了巨大成功，但其对胶质母细胞瘤（GBM）的疗效仍然有限。免疫抑制的肿瘤微环境（TME）和免疫治疗药物进入肿瘤的贫穷渗透都导致了抗胶质瘤免疫不良。在此，我们开发了一种具有声激活特性的可注射的前药负载水凝胶传递系统，用于声动力治疗（SDT）诱导的GBM治疗免疫调节。通过在TME中的藻酸盐溶液与Ca2+的配位，形成了内源前药藻酸盐水凝胶（APN），其中包含半导电聚合物纳米粒子（SPNs）和由单线态氧（1O2）可切割连接物连接的NLG919前药。 SPNs作为超声波（US）辐照产生1O2的敏感物质，用于SDT。产生的1O2既诱导免疫细胞死亡，又断裂1O2可切割连接物以精确激活NLG919前药。由于通过色胺酸代谢诱导剂2,3-二氧酶依赖的蓝靛酸化作用的逆转，抗肿瘤免疫力显著增强。这种智能前药水凝胶平台显著抑制了胶质瘤切取小鼠中的肿瘤生长。总体而言，本研究为针对GBM的精确声免疫疗法提供了一种声激活水凝胶平台。

Although immunotherapy has achieved great success in the treatment of a variety of tumors, its efficacy for glioblastoma (GBM) is still limited. Both the immunosuppressive tumor microenvironment (TME) and poor penetration of immunotherapeutic agents into tumors contributed to the poor anti-glioma immunity. Herein, we develop an injectable prodrug-loaded hydrogel delivery system with sono-activatable properties for sonodynamic therapy (SDT)-triggered immunomodulation for GBM treatment. The prodrug alginate hydrogels (APN), which contain semiconducting polymer nanoparticles (SPNs) and the NLG919 prodrug linked by singlet oxygen (1O2)-cleavable linkers, are in situ formed via coordination of alginate solution with Ca2+ in the TME. SPNs serve as sonosensitizers to produce 1O2 upon ultrasound (US) irradiation for SDT. The generated 1O2 not only induce immunogenic cell death, but also break 1O2-cleavable linkers to precisely activate the NLG919 prodrug. Antitumor immunity is significantly amplified due to the reversal of immunosuppression mediated by indolamine 2,3-dioxygenase-dependent tryptophan metabolism. This smart prodrug hydrogel platform potently inhibits tumor growth in orthotopic glioma-bearing mice. Collectively, this work provides a sono-activatable hydrogel platform for precise sono-immunotherapy against GBM.