Paclitaxel and Nlg919 Co-loaded MnO2–Albumin Nanoparticles for Synergistic Chemoimmune Cancer Therapy

The tumor hypoxic core and immunosuppressive environment pose significant challenges to the effectiveness of anticancer therapy. Consequently, there is a growing emphasis on strategies aimed at enhancing tumor tissue oxygenation and restoring the host immune response. Based on this, we proposed the synthesis of two bioresponsive dimeric prodrugs of paclitaxel, a chemotherapeutic agent, and Nlg919, an IDO1 inhibitor, that were coloaded into MnO2-decorated albumin nanoparticles, dNlgdPtx-mHSA. This approach was conceived to exploit tumor microenvironment (TME) features for achieving a precise and targeted therapeutic effect through synergistic chemoimmune therapy. Moreover, it sought to mitigate hypoxia by leveraging the nanozyme activity of MnO2, which catalyzed the decomposition of excess hydrogen peroxide within the tumor milieu into molecular oxygen. Preliminary results demonstrated that the nanosystem exhibited excellent controlled drug release, remarkably reduced cell viability in both two-dimensional (2D) and three-dimensional (3D) models, and restored immune response through immune cell death induction and IDO1 inhibition. Finally, dNlgdPtx-mHSA showed promising potential to promote relief from tumor hypoxia and potential involvement in the repolarization of tumor-associated macrophages toward the M1 antitumor phenotype.肿瘤缺氧核心区域与免疫抑制性微环境，会对抗癌治疗的临床效果造成显著挑战。为此，科研界日益重视旨在改善肿瘤组织氧合状态、重建宿主免疫应答的治疗策略。基于此，本研究合成了两种生物响应型二聚前药：化疗药物紫杉醇（paclitaxel）与吲哚胺2,3-双加氧酶1（IDO1）抑制剂Nlg919，并将二者共负载于经二氧化锰（MnO₂）修饰的白蛋白纳米粒dNlgdPtx-mHSA中。该设计旨在利用肿瘤微环境（Tumor Microenvironment, TME）的特征，通过协同化学免疫治疗实现精准靶向的治疗效果；同时借助二氧化锰的纳米酶（nanozyme）活性缓解肿瘤缺氧，其可催化肿瘤微环境中过量过氧化氢分解为分子氧。初步实验结果表明，该纳米系统具备优异的药物控释性能，可显著降低二维（2D）及三维（3D）细胞模型的细胞存活率，并通过诱导免疫细胞死亡与抑制IDO1活性重建机体免疫应答。最终，dNlgdPtx-mHSA展现出良好的缓解肿瘤缺氧潜力，且有望通过促进肿瘤相关巨噬细胞极化为M1型抗肿瘤表型，发挥潜在的治疗价值。