Concurrent localized radiotherapy and systemic chemotherapy are standards of care for many cancers, but these treatment regimens cause severe adverse effects in many patients. Herein, we report the design of a mixed-ligand nanoscale metal–organic framework (nMOF) with the ability to simultaneously enhance radiotherapeutic effects and trigger the release of a potent chemotherapeutic under X-ray irradiation. We synthesized a new functional quaterphenyl dicarboxylate ligand conjugated with SN38 (H2QP-SN) via a hydroxyl radical-responsive covalent linkage. Because of the similar length of QP-SN and bis(p-benzoato)porphyrin (DBP) ligands, QP-SN was incorporated into Hf-DBP nMOF to afford a novel multifunctional mixed-ligand Hf-DBP-QP-SN nMOF with good biocompatibility. Hf-DBP-QP-SN not only enhances radiation damage to tumors via a unique radiotherapy-radiodynamic therapy (RT-RDT) process but also increases ·OH generation from radiolysis with electron-dense Hf12 secondary building units (SBUs) to release SN38 from Hf-DBP-QP-SN for chemotherapy. Elevated levels of hydrogen peroxide in the tumor microenvironment further stimulate the release of SN38 by enhancing ·OH generation under X-ray irradiation. With low doses of X-ray irradiation, Hf-DBP-QP-SN suppressed the growth of CT26 colon and 4T1 breast tumors by 93.5% and 95.2%, respectively, without any sign of general toxicity. Our study highlights the potential of using ionizing radiation-mediated chemistry for on-demand activation of nanotherapeutics for synergistic radiotherapy and chemotherapy without causing severe adverse effects.

Wenyao Zhen

Ziwan Xu

Yibin Mao

Caroline McCleary

Xiaomin Jiang

Ralph R. Weichselbaum

Wenbin Lin

Journal of the American Chemical Society

美国化学学会杂志 (JACS) 成立于 1879 年，是美国化学学会的旗舰期刊，也是世界上所有化学和科学交叉领域的杰出期刊。该期刊致力于出版基础知识研究论文，每年发表约 19,000 页的文章、通讯和展望。每周出版，JACS 提供化学领域必不可少的研究。化学领域被引用次数最多的期刊，美国化学学会杂志 (JACS) 共收到 462,510引用次数和影响因子增加到 11.444，如 2013 年期刊引文报告®（汤森路透，2014 年）报告的那样。JACS 在出版涵盖所有化学领域的原创研究和每年超过 2,000 篇文章的期刊中的影响因子排名第一

The Journal of the American Chemical Society (JACS), established in 1879, is the flagship journal of the American Chemical Society and a leading journal in the fields of chemistry and interdisciplinary sciences worldwide. The journal focuses on fundamental research, publishing approximately 19,000 pages of articles, communications, and perspectives each year. JACS is published weekly and provides essential resources for research in the field of chemistry. According to the 2013 Journal Citation Reports (Thomson Reuters, 2014), JACS is the most cited journal in chemistry, with a total citation count of 462,510 and an impact factor of 11.444, ranking first among journals publishing original research across all areas of chemistry, with over 2,000 articles published annually.

《美国化学学会杂志》（Journal of the American Chemical Society，简称 JACS）成立于 1879 年，是美国化学学会的旗舰期刊，也是全球化学及相关交叉学科领域的顶尖期刊。该期刊专注于基础研究，年均发表约 19,000 页的研究论文、通讯和展望。JACS 每周出版，为化学领域的研究提供了不可或缺的资源。根据 2013 年的期刊引文报告（汤森路透，2014 年），JACS 是被引用次数最多的化学期刊，累计引用次数达到 462,510，影响因子高达 11.444，位居所有化学领域原创研究期刊之首，每年发表超过 2,000 篇文章。

Category	Quartile
化学	1
化学, 化学综合	1

Nanoscale Mixed-Ligand Metal–Organic Framework for X-ray Stimulated Cancer Therapy

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Category	Quartile
CHEMISTRY, MULTIDISCIPLINARY	1