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Proton Sponge Nanocomposites for Synergistic Tumor Elimination via Autophagy Inhibition-Promoted Cell Apoptosis and
Yifan Duan1, Wei Zhang2, Yi Ouyang1
1Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, School of Materials and Energy, Southwest University, Chongqing 400715, China.
Abstract:
Cytoprotective autophagy and an immunosuppressive tumor microenvironment (TME) are two positive promoters for tumor proliferation and metastasis that severely hinder therapeutic efficacy. Inhibiting autophagy and reconstructing TME toward macrophage activation simultaneously are of great promise for effective tumor elimination, yet are still a huge challenge. Herein, a kind of dendrimer-based proton sponge nanocomposites was designed and constructed for tumor chemo/chemodynamic/immunotherapy through autophagy inhibition-promoted cell apoptosis and macrophage repolarization-enhanced immune response. These obtained nanocomposites contain a proton sponge G5AcP dendrimer, a Fenton-like agent Cu(II), and chemical drug doxorubicin (DOX). When accumulated in tumor regions, G5AcP can act as an immunomodulator to realize deacidification-promoted macrophage repolarization toward antitumoral type, which then secretes inflammatory cytokines to activate T cells. They also regulate intracellular lysosomal pH to inhibit cytoprotective autophagy. The released Cu(II) and DOX can induce aggravated damage through a Fenton-like reaction and chemotherapeutic effect in this autophagy-inhibition condition. Tumor-associated antigens are released from these dying tumor cells to promote the maturity of dendritic cells, further activating T cells. Effective tumor elimination can be achieved by this dendrimer-based therapeutic strategy, providing significant guidance for the design of a promising antitumor nanomedicine.
Insights
This study presents a novel dendrimer-based nanocomposite that simultaneously inhibits tumor cell autophagy and reprograms the tumor microenvironment (TME) to enhance anti-tumor immunity and therapeutic efficacy.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Cancer Therapy
Background:
- Cytoprotective autophagy and immunosuppressive tumor microenvironments (TME) promote tumor growth and metastasis, limiting treatment effectiveness.
- Simultaneously inhibiting autophagy and reprogramming the TME for macrophage activation is a promising but challenging strategy for tumor elimination.
Purpose of the Study:
- To design and construct dendrimer-based proton sponge nanocomposites for combined chemo/chemodynamic/immunotherapy.
- To investigate the strategy of autophagy inhibition-promoted apoptosis and macrophage repolarization-enhanced immune response for effective tumor elimination.
Main Methods:
- Developed G5AcP dendrimer-based nanocomposites incorporating Cu(II) and doxorubicin (DOX).
- Evaluated the nanocomposites' ability to act as immunomodulators, inhibit autophagy, and induce tumor cell damage via Fenton-like reactions and chemotherapy.
- Assessed the impact on macrophage repolarization, T cell activation, and dendritic cell maturation.
Main Results:
- The nanocomposites effectively promoted macrophage repolarization towards an anti-tumoral phenotype, enhancing immune response.
- Intracellular lysosomal pH regulation by G5AcP inhibited cytoprotective autophagy, sensitizing tumor cells to therapy.
- The combination of inhibited autophagy, released Cu(II), and DOX led to aggravated tumor cell damage and effective tumor elimination.
Conclusions:
- The developed dendrimer-based therapeutic strategy shows significant promise for effective tumor elimination.
- This approach provides valuable guidance for designing advanced nanomedicines targeting both tumor cells and the TME.
