基因疗法为重大人类疾病提供了潜在的变革策略。然而，基因疗法面临的一个关键挑战是开发一种能将基因传递到特定组织的有效策略。在这里，我们报告了一种新型的病毒样纳米粒子，生物正交工程病毒样重组生物体（reBiosome），用于有效治疗癌症和炎症性疾病的基因疗法。首先，通过位点特异性密码子突变，在eBiosome的衣壳溶酶体溶菌蛋白上合理位点上展示4-偶氮-L-苯丙氨酸来制备突变病毒样生物体（mBiosome），然后通过生物正交化学将点击弱酸响应性亲水性聚合物连接到mBiosome上，制备出reBiosome。结果表明，reBiosome表现出较低的病毒样免疫原性、延长的血液循环时间和对弱酸性病灶（如肿瘤和关节炎组织）的增强基因传递效率。此外，reBiosome通过分别传递基因编辑和沉默系统，在乳腺癌和关节炎中展示出强大的治疗效果。总之，本研究开发了一种用于癌症和炎症性疾病基因疗法的通用、安全且高效的平台。©2023年上海交通大学。

Gene therapy offers potentially transformative strategies for major human diseases. However, one of the key challenges in gene therapy is developing an effective strategy that could deliver genes into the specific tissue. Here, we report a novel virus-like nanoparticle, the bioorthgonal engineered virus-like recombinant biosome (reBiosome), for efficient gene therapies of cancer and inflammatory diseases. The mutant virus-like biosome (mBiosome) is first prepared by site-specific codon mutation for displaying 4-azido-L-phenylalanine on vesicular stomatitis virus glycoprotein of eBiosome at a rational site, and the reBiosome is then prepared by clicking weak acid-responsive hydrophilic polymer onto the mBiosome via bioorthogonal chemistry. The results show that the reBiosome exhibits reduced virus-like immunogenicity, prolonged blood circulation time and enhanced gene delivery efficiency to weakly acidic foci (like tumor and arthritic tissue). Furthermore, reBiosome demonstrates robust therapeutic efficacy in breast cancer and arthritis by delivering gene editing and silencing systems, respectively. In conclusion, this study develops a universal, safe and efficient platform for gene therapies for cancer and inflammatory diseases.© 2023. Shanghai Jiao Tong University.