State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Mater Horiz. 2024 May 20;11(10):2406-2419. doi: 10.1039/d3mh01844j.
Enzymes provide a class of potential options to treat cancer, while the precise regulation of enzyme activities for effective and safe therapeutic actions has been poorly reported. Dual-enzyme decorated semiconducting polymer nanoagents for second near-infrared (NIR-II) photoactivatable ferroptosis-immunotherapy are reported in this study. Such nanoagents (termed SPH) consist of hemoglobin (Hb)-based semiconducting polymer (SP@Hb), adenosine deaminase (ADA) and glucose oxidase (GOx) with loadings in a thermal-responsive nanoparticle shell. NIR-II photoactivation of SPH results in the generation of heat to trigger on-demand releases of two enzymes (ADA and GOx) destroying the thermal-responsive nanoparticle shells. In the tumor microenvironment, GOx oxidizes glucose to form hydrogen peroxide (HO), which promotes the Fenton reaction of iron in SP@Hb, resulting in an enhanced ferroptosis effect and immunogenic cell death (ICD). In addition, ADA degrades high-level adenosine to reverse the immunosuppressive microenvironment, thus amplifying antitumor immune responses. NIR-II photoactivatable ferroptosis-immunotherapy, SPH shows an improved effect to absolutely remove bilateral tumors and effectively suppress tumor metastases in subcutaneous 4T1 breast cancer models. This study presents a dual-enzyme-based nanoagent with controllable therapeutic actions for effective and precise cancer therapy.
酶为癌症治疗提供了一类潜在的选择，然而，对于有效和安全的治疗作用，酶活性的精确调控仍鲜有报道。本研究报道了用于近红外二区（NIR-II）光激活铁死亡-免疫治疗的双酶修饰的半导体聚合物纳米制剂。这种纳米制剂（称为 SPH）由基于血红蛋白（Hb）的半导体聚合物（SP@Hb）、腺苷脱氨酶（ADA）和葡萄糖氧化酶（GOx）组成，负载在热响应纳米颗粒壳中。SPH 的 NIR-II 光激活会产生热量，从而触发两种酶（ADA 和 GOx）的按需释放，破坏热响应纳米颗粒壳。在肿瘤微环境中，GOx 将葡萄糖氧化生成过氧化氢（HO），促进 SP@Hb 中铁的芬顿反应，从而增强铁死亡效应和免疫原性细胞死亡（ICD）。此外，ADA 将高水平的腺苷降解，逆转免疫抑制微环境，从而增强抗肿瘤免疫反应。近红外二区光激活铁死亡-免疫治疗，SPH 在皮下 4T1 乳腺癌模型中表现出改善的效果，可以彻底消除双侧肿瘤并有效抑制肿瘤转移。本研究提出了一种基于双酶的纳米制剂，具有可控的治疗作用，可实现有效的精准癌症治疗。
