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.