小分子前药纳米组装技术在降低脱靶毒性方面具有独特优势，已广泛应用于抗肿瘤药物递送。然而，前药激活仍然是发挥治疗作用的限速步骤，这需要快速达到游离药物的最低有效浓度。幸运的是，我们发现一种天然化合物（BL-193）在无效剂量浓度下选择性提高乳腺癌细胞对鬼臼毒素（PPT）的化疗敏感性。基于此，我们建议将前药纳米组装与化疗增敏相结合，以充分释放PPT的化疗潜力。具体而言，通过将9-芴基甲醇(Fmoc-OH)与通过二硫键连接的PPT偶联来合成PPT的氧化还原敏感前药(PSSF)。有趣的是，具有 π 共轭结构的 PSSF 很容易与 BL-193 共组装成稳定的纳米组装体。值得注意的是，BL-193 作为一种出色的化疗增敏剂，可为 PPT 创建超低剂量化疗窗口。此外，前药设计和精确的混合纳米组装可以很好地控制脱靶毒性。正如预期的那样，这种 BL-193 赋能的前药纳米组装体能够引发有效的抗肿瘤反应。这项研究为放大化疗疗效-毒性益处提供了一种新的范例。© 2024 由 Elsevier B.V. 代表沉阳药科大学出版。

Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug delivery. However, prodrug activation remains a rate-limiting step for exerting therapeutic actions, which requires to quickly reach the minimum valid concentrations of free drugs. Fortunately, we find that a natural compound (BL-193) selectively improves the chemotherapy sensitivity of breast cancer cells to podophyllotoxin (PPT) at ineffective dose concentrations. Based on this, we propose to combine prodrug nanoassembly with chemotherapy sensitization to fully unleash the chemotherapeutic potential of PPT. Specifically, a redox-sensitive prodrug (PSSF) of PPT is synthesized by coupling 9-fluorenyl-methanol (Fmoc-OH) with PPT linked via disulfide bond. Intriguingly, PSSF with a π-conjugated structure readily co-assembles with BL-193 into stable nanoassembly. Significantly, BL-193 serves as an excellent chemosensitizer that creates an ultra-low-dose chemotherapeutic window for PPT. Moreover, prodrug design and precise hybrid nanoassembly well manage off-target toxicity. As expected, such a BL-193-empowered prodrug nanoassembly elicits potent antitumor responses. This study offers a novel paradigm to magnify chemotherapy efficacy-toxicity benefits.© 2024 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University.