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Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy.

ACS Nano(2024)SCI 1区

Wuhan Univ | Shenzhen Peoples Hosp | Southern Med Univ | Univ Western Australia | Univ Hong Kong | Guizhou Med Univ

Cited 3|Views36
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.
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nanobody,midkine,immunotherapy,targeted therapy,pancreatic ductal adenocarcinoma
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要点】:本研究设计了一种基于中胚层神经元抑制因子的纳米平台,通过针对胰腺导管腺癌 (PDAC) 的肿瘤特异性抗体,将光敏性聚合物纳米颗粒高效输送至肿瘤微环境 (TME),并在光激发下产生丰富的活性氧物质 (ROS),以实现精确的光免疫治疗,同时重塑免疫抑制的 TME。

方法】:通过合成的纳米复合材料,实现了对 PDAC 肿瘤的多模式成像 (荧光和光声成像),并通过光激发下的 ROS,诱导肿瘤细胞凋亡和免疫原性细胞死亡,最终阻止肿瘤的进展,并增加淋巴细胞的浸润。

实验】:通过针对 PDAC 肿瘤特异性抗体的纳米颗粒制备的纳米平台,在光激发下实现了肿瘤的精确光免疫治疗,并引入 PD-1 检查点抑制剂实现更好的抗肿瘤效果,显著延长小鼠的生存时间。