Implantable Bioresponsive Nanoarray Enhances Postsurgical Immunotherapy by Activating Pyroptosis and Remodeling Tumor Microenvironment,Advanced Functional Materials

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Implantable Bioresponsive Nanoarray Enhances Postsurgical Immunotherapy by Activating Pyroptosis and Remodeling Tumor Microenvironment
Advanced Functional Materials ( IF 18.5 ) Pub Date : 2020-09-18 , DOI: 10.1002/adfm.202005747
Hongjuan Zhao _{1,

2} , Qingling Song _{1,

2} , Cuixia Zheng _{1,

2} , Beibei Zhao _{1,

2} , Lixia Wu ₁ , Qianhua Feng ₁ , Zhenzhong Zhang _{1,

2,

3} , Lei Wang _{1,

2,

3}

Affiliation

Despite the potential of drug‐loaded scaffolds for tumor recurrence and metastasis (TRM) postoperation, their therapeutic benefits are limited by marked immunosuppressive tumor microenvironment (ITME) and drug‐related untargeted toxicity. Herein, an innovative implantable bioresponsive nanoarray is developed to overcome the above limitations. Chemotherapeutics doxorubicin (DOX) and the epigenetic modulator JQ1 are coloaded into tumor‐targeting nanoparticles (HP‐DOX/JQ1 NPs), which are then linked up through a bio‐responsive linker to construct the nanoarray loading with another part of JQ1 (DOX/JQ1‐IBRN). Under high level of H₂O₂ in TME, the implanted DOX/JQ1‐IBRN disaggregates and release JQ1 while generating small‐sized HP‐DOX/JQ1 NPs for realizing ITME modulation and tumor‐targeting therapy. JQ1 selectively blocks programmed death‐ligand 1 (PD‐L1) mediated immune evasion and reduces regulatory T cells (Tregs)/‐disruptive effect to facilitate immunopositivity. HP‐DOX/JQ1 NPs destroy residual tumor precisely and trigger gasdermin E (GSDME)‐dependent pyroptosis, further enhancing the number and functions of tumor‐infiltrating T lymphocytes for antitumor immunity. It is demonstrated that DOX/JQ1‐IBRN prevents post‐surgical TRM and prolongs survival in multiple murine tumor models with negligible toxicity. This cooperation in tumor accurate pyroptosis and ITME conversion through the implantable nanoarray (a simple, valid, and safe scaffold) is expected to provide crucial insights for post‐surgical treatment.

中文翻译：

植入式生物响应性纳米阵列通过激活细胞凋亡和重塑肿瘤微环境来增强术后免疫治疗。

尽管载药的支架可能在术后复发和转移（TRM），但其治疗益处受到明显的免疫抑制性肿瘤微环境（ITME）和药物相关的非靶向毒性的限制。在本文中，开发了创新的可植入生物响应性纳米阵列以克服上述限制。将化学疗法阿霉素（DOX）和表观遗传调节剂JQ1共加载到靶向肿瘤的纳米颗粒（HP‐DOX / JQ1 NP）中，然后通过生物反应性接头将其连接起来，以构建与JQ1另一部分（DOX / JQ1-IBRN）。在高水平的H ₂ O _2下在TME中，植入的DOX / JQ1-IBRN分解并释放JQ1，同时生成小型HP-DOX / JQ1 NP，以实现ITME调节和肿瘤靶向治疗。JQ1选择性阻断程序性死亡配体1（PD-L1）介导的免疫逃逸，并降低调节性T细胞（Tregs）/破坏作用，以促进免疫阳性。HP‐DOX / JQ1 NP精确地破坏了残留的肿瘤，并触发了依赖Gasdermin E（GSDME）的热解，进一步增强了肿瘤浸润性T淋巴细胞的抗肿瘤免疫力。结果表明，DOX / JQ1-IBRN可以在毒性很小的情况下在多种鼠类肿瘤模型中预防术后TRM并延长生存期。通过可植入的纳米阵列（简单，有效，

更新日期：2020-09-18

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