Paclitaxel and Nlg919 Co-Loaded MnO2-Albumin Nanoparticles for Synergistic Chemo-Immune Cancer Therapy

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Applied Nano Materials, 8, 9, 4911–4925 (DOI: 10.1021/acsanm.5c00589) © 2025 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/articlesonrequest/AOR-WSYH3DVG79C6RXHMQQVQThis Manuscript version is made available under the CC-BY-NC-ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/ ABSTRACT The tumor hypoxic core and the 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 co-loaded 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 chemo-immune therapy. Moreover, it seeks to mitigate hypoxia by leveraging the nanozyme activity of MnO2, which catalyzes 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 2D and 3D models and restored immune response through immune cell death induction and IDO1 inhibition. Finally, dNlgdPtx-mHSA showed promising capability to promote relief from tumor hypoxia, and a potential involvement in the repolarization of tumor associated macrophages towards the M1 antitumor phenotype.