Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

中文翻译：

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源自患者的自体耗尽纳米 T 细胞利用肿瘤免疫逃避来进行有效的癌症治疗

表面修饰纳米平台的主动靶向可以使纳米粒子在肿瘤内更精确和更高的积累，从而增强药物输送和成功癌症治疗的功效。然而，表面功能化涉及复杂的程序，增加了成本和时间，给临床实施带来了挑战。仿生纳米颗粒（BNP）已成为独特的药物输送平台，克服了主动靶向纳米颗粒的局限性。然而，涂有未修饰细胞的 BNP 显示出功能降低，例如特异性肿瘤靶向，从而降低了治疗效果。这些挑战可以通过设计用于 BNP 涂层的非患者来源的细胞来克服，但这些都是复杂且具有成本效益的方法，阻碍了其更广泛的临床应用。在这里，我们提出了一种免疫驱动的策略来改善纳米治疗药物对肿瘤的递送。我们独特的视角利用 T 细胞耗竭和肿瘤免疫逃避，开发出一种突破性的新型 BNP，该 BNP 是由三阴性乳腺癌 (TNBC) 患者的耗竭 T 细胞 (NExT) 通过特定培养方法制成，无需复杂的工程。 NExT 是通过在体外通过急性激活耗尽的 TNBC 衍生 T 细胞涂覆 PLGA（聚乳酸-乙醇酸）纳米颗粒而产生的。通过动态光散射、电泳光散射和透射电子显微镜对 NExT 进行物理化学表征，并通过流式细胞术对免疫检查点受体进行保存和定向。在体外 TNBC 细胞系中评估了负载化疗的 NExT 的疗效。在 CD1 小鼠中产生体内毒性。 NExT 的生物分布和治疗活性是在免疫缺陷小鼠的细胞系和自体患者来源的异种移植物中测定的。我们报告了一种具有良好性能的经济有效的方法，该方法提供天然赋予免疫检查点受体（PD1、LAG3、TIM3）的NExT，通过接合同源配体增强特定肿瘤靶向，增强化疗的治疗效果，并破坏PD1/PDL1轴以类似免疫疗法的方式。源自患者的自体 NExT 显示出异常的肿瘤内积聚，提高了化疗指数和效率，并在 PDL1+ 源自患者的三阴性乳腺癌异种移植模型中靶向肿瘤基质。这些优势凸显了自体患者来源的 NExT 彻底改变定制过继性癌症纳米疗法和化学免疫疗法的潜力，这支持了自体患者来源的 NExT 的广泛临床应用。