免疫抑制的肿瘤微环境和有限的瘤内渗透在很大程度上限制了肿瘤治疗的结果。在此，我们报告了一种基于 DNA 结构的定制纳米平台，具有惊人的肿瘤穿透能力，可用于体内免疫抑制肿瘤微环境的靶向重塑。在我们的设计中，化学免疫调节剂（吉西他滨）可以通过活性氧（ROS）敏感的连接子精确地移植到DNA序列中。自组装后，吉西他滨嫁接的DNA结构可以在每个顶点上位点特异性地组织legumain可激活的蜂毒肽前肽（promelittin）进行瘤内递送，并进一步作为模板加载光敏剂（亚甲蓝）以产生ROS。定制的DNA纳米平台可以通过激光照射实现肿瘤细胞的靶向积累、高度改善的瘤内渗透以及高效的免疫原性细胞死亡。最后，通过减少多型免疫抑制细胞、增强肿瘤内细胞毒性淋巴细胞的浸润，可以成功重塑免疫抑制肿瘤微环境。这种合理开发的多功能 DNA 纳米平台为肿瘤治疗的发展提供了新的途径。© 2024 Wiley‐VCH GmbH。

Immunosuppressive tumor microenvironment and limited intratumoral permeation have largely constrained the outcome of tumor therapy. Herein, we report a tailored DNA structure-based nanoplatform with striking tumor-penetrating capability for targeted remodeling of immunosuppressive tumor microenvironment in vivo. In our design, chemo-immunomodulator (gemcitabine) can be precisely grafted in DNA sequences via a reactive oxygen species (ROS)-sensitive linker. After self-assembly, the gemcitabine-grafted DNA structure can site-specifically organize legumain-activatable melittin pro-peptide (promelittin) on each vertex for intratumoral delivery and further function as the template to load photosensitizers (methylene blue) for ROS production. The tailored DNA nanoplatform can achieve targeted accumulation, highly improved intratumoral permeation, and efficient immunogenic cell death of tumor cells by laser irradiation. Finally, the immunosuppressive tumor microenvironment can be successfully remodeled by reducing multi-type immunosuppressive cells and enhancing the infiltration of cytotoxic lymphocytes in the tumor. This rationally developed multifunctional DNA nanoplatform provides a new avenue for the development of tumor therapy.© 2024 Wiley‐VCH GmbH.