Insufficient delivery of therapeutic agents into solid tumors by systemic administration remains a major challenge in cancer treatment. Secreted protein acidic and rich in cysteine (SPARC) has high binding affinity to albumin and has been shown to enhance the penetration and uptake of albumin-based drug carriers in tumors. Here, we developed a strategy to alter the tumor microenvironment (TME) by upregulating SPARC to enhance the delivery efficiency of albumin-based drug carriers into tumors. We prepared albumin nanoparticles encapsulating an NF-κB controllable CRISPR activation system (SP-NPs). SP-NPs achieved tumor-selective SPARC upregulation by responding to the highly activated NF-κB in tumor cells. Whereas a single dose of SP-NPs only modestly upregulated SPARC expression, serial administration of SP-NPs created a positive feedback loop that induced progressive increases in SPARC expression as well as tumor cell uptake and tumor penetration of the nanoparticles in vitro, in organoids, and in subcutaneous tumors in vivo. Additionally, pre-treatment with SP-NPs significantly enhanced the anti-tumor efficacy of Abraxane, a commercialized albumin-bound paclitaxel nanoformulation. Our data provide evidence that modulating SPARC in the TME can enhance the efficiency of albumin-based drug delivery to solid tumors, which may result in new strategies to increase the efficacy of nanoparticle-based cancer drugs.

通过全身给药将治疗剂不足以递送至实体瘤中仍然是癌症治疗中的主要挑战。富含半胱氨酸的酸性分泌蛋白 (SPARC) 与白蛋白具有高结合亲和力，已被证明可以增强肿瘤中基于白蛋白的药物载体的渗透和吸收。在这里，我们开发了一种通过上调 SPARC 来改变肿瘤微环境 (TME) 的策略，以提高基于白蛋白的药物载体向肿瘤的递送效率。我们制备了封装 NF-κB 可控 CRISPR 激活系统 (SP-NP) 的白蛋白纳米颗粒。 SP-NPs 通过响应肿瘤细胞中高度激活的 NF-κB 来实现肿瘤选择性 SPARC 上调。单剂量的 SP-NP 仅适度上调 SPARC 表达，而连续施用 SP-NP 则创建了一个正反馈回路，可诱导 SPARC 表达逐渐增加以及体外、类器官中肿瘤细胞对纳米颗粒的摄取和肿瘤渗透。以及体内皮下肿瘤。此外，SP-NP 预处理显着增强了 Abraxane（一种商品化的白蛋白结合紫杉醇纳米制剂）的抗肿瘤功效。我们的数据提供的证据表明，调节 TME 中的 SPARC 可以提高基于白蛋白的药物递送至实体瘤的效率，这可能会产生提高基于纳米颗粒的癌症药物疗效的新策略。