Purpose

Sonodynamic therapy (SDT) is a promising strategy as an “in situ vaccine” to enhance activation of antitumor immune responses in solid tumors. However, the dense extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) lead to hypoxia and limited penetration of most drugs, aggravating the immunosuppressive tumor microenvironment and limiting the efficacy of synergistic sonodynamic immunotherapy. Therefore, it is essential to regulate ECM in order to alleviate tumor hypoxia and enhance the efficacy of sonodynamic immunotherapy for PDAC.

Methods

The CPIM nanoplatform, consisting of a macrophage membrane-coated oxygen and drug delivery system (CM@PFOB-ICG-α-Mangostin), was synthesized using ultrasound and extrusion methods. The in vivo homologous targeting and hypoxia alleviation capabilities of CPIM were evaluated through near-infrared (NIR) imaging and photoacoustic (PA) imaging. The tumor growth inhibition potential and ability to reprogram the tumor microenvironment by the CPIM nanoplatform were also investigated.

Results

Co-delivery of α-Mangostin inhibits CAFs and enhances stromal depletion, thereby facilitating better infiltration of macromolecules. Additionally, the nanoemulsion containing perfluorocarbon (PFC) can target tumor cells and accumulate within them through homologous targeting. The US irradiation results in the rapid release of oxygen, serving as a potential source of sonodynamic therapy for hypoxic tumors. Moreover, CPIM reshapes the immunosuppressive microenvironment increasing the population of cytotoxic T lymphocytes (CTLs), and enhancing their anti-tumor immune response through the use of anti-PDL1 antibodies to block immune checkpoints.

Conclusion

The present study offers a potential strategy for the co-delivery of oxygen and α-Mangostin, aiming to enhance the penetration of tumors to improve SDT. This approach effectively addresses the existing limitations of immune checkpoint blockade (ICB) treatment in solid tumors, while simultaneously boosting the immune response through synergistic sonodynamic immunotherapy.

中文翻译：

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利用膜伪装纳米平台增强组织渗透性以改善胰腺导管腺癌的声动力学免疫治疗

 目的

声动力疗法 （SDT） 是一种很有前途的“原位疫苗”策略，可增强实体瘤抗肿瘤免疫反应的激活。然而，胰腺导管腺癌 （PDAC） 中致密的细胞外基质 （ECM） 导致缺氧和大多数药物的渗透受限，加剧了免疫抑制性肿瘤微环境并限制了协同声动力学免疫疗法的疗效。因此，为了缓解肿瘤缺氧和增强声动力免疫疗法对 PDAC 的疗效，调节 ECM 至关重要。

 方法

CPIM 纳米平台由巨噬细胞膜包被的氧气和药物递送系统 （C M@PFOB-I CG-α-M angostin） 组成，采用超声和挤出方法合成。通过近红外 （NIR） 成像和光声 （PA） 成像评价 CPIM 的体内同源靶向和缺氧缓解能力。还研究了 CPIM 纳米平台对肿瘤生长抑制的潜力和重编程肿瘤微环境的能力。

 结果

α-Mangostin 的共同递送抑制 CAFs 并增强基质耗竭，从而促进大分子更好地浸润。此外，含有全氟化碳 （PFC） 的纳米乳剂可以靶向肿瘤细胞并通过同源靶向在肿瘤细胞内积累。US 照射导致氧气快速释放，是缺氧性肿瘤声动力学治疗的潜在来源。此外，CPIM 重塑免疫抑制微环境，增加细胞毒性 T 淋巴细胞 （CTL） 的数量，并通过使用抗 PDL1 抗体阻断免疫检查点来增强其抗肿瘤免疫反应。

 结论

本研究为氧气和 α-Mangostin 的共同递送提供了一种潜在的策略，旨在增强肿瘤的渗透性以改善 SDT。这种方法有效地解决了实体瘤免疫检查点阻断 （ICB） 治疗的现有局限性，同时通过协同声动力学免疫疗法增强免疫反应。