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Updated: Apr 30, 2026
An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
ROS-responsive resiquimod prodrug nanoparticles for macrophage reprogramming and enhanced immune checkpoint inhibitor
Rui Geng1, Haojie Shang2, Zhiqiang Chen3
1Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Hubei Research Center for Biomaterials and Medical Protective Materials, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), Wuhan, 430074, China.
Abstract:
Bladder cancer remains a formidable challenge, especially for patients who fail to respond adequately to immune checkpoint inhibitors (ICIs). The suboptimal efficacy of current treatments underscores an urgent need for more effective immunomodulatory strategies. Here, we propose a ROS-responsive resiquimod (R848) prodrug (R-P) that improves drug delivery and reshapes the immunosuppressive tumor microenvironment. Clinical data from The Cancer Genome Atlas and patient samples underscore the therapeutic value of targeting CD206 and TLR7/8 to repolarize tumor-associated macrophages. The prodrug R-P is created by conjugating a phenylboronic acid pinacol ester moiety to R848 via a succinic anhydride linker, enabling the prodrug to remain stable in systemic circulation while releasing its parent compound in the oxidative tumor microenvironment, thereby minimizing off-target effects. Further, mannose-functionalized nanoparticles (R-P@APM-DPs) achieve an impressive loading capacity of R848 (34.3 %) and exhibit robust ROS-responsive release. In a murine MB49 bladder cancer model, R-P@APM-DPs significantly reduce tumor growth, enhance M1 macrophages, and increase CD8+ and CD4+ T cells, while decreasing the number of immunosuppressive cells. Notably, combination therapy with anti-PD-1 leads to a potent anticancer response in both MB49-bearing mice and patient-derived organoids. This synergy highlights the translational potential of a ROS-responsive prodrug approach for enhancing ICI-based immunotherapies.
Insights
This study introduces a novel ROS-responsive resiquimod prodrug, R-P, encapsulated in nanoparticles. This approach enhances drug delivery and boosts anti-cancer immunity, particularly when combined with immune checkpoint inhibitors for bladder cancer treatment.
Area of Science:
- Immunology
- Oncology
- Materials Science
Background:
- Bladder cancer poses significant challenges, especially for patients unresponsive to immune checkpoint inhibitors (ICIs).
- Current treatments necessitate improved immunomodulatory strategies to enhance efficacy.
- Targeting CD206 and TLR7/8 shows therapeutic potential for repolarizing tumor-associated macrophages.
Purpose of the Study:
- To develop a reactive oxygen species (ROS)-responsive resiquimod (R848) prodrug (R-P) for improved bladder cancer immunotherapy.
- To enhance drug delivery and modulate the immunosuppressive tumor microenvironment.
- To evaluate the synergistic effects of the prodrug with anti-PD-1 therapy.
Main Methods:
- Conjugation of a phenylboronic acid pinacol ester to R848 via a succinic anhydride linker to create the R-P prodrug.
- Encapsulation of R-P into mannose-functionalized nanoparticles (R-P@APM-DPs) for targeted delivery.
- In vivo studies using a murine MB49 bladder cancer model and in vitro studies with patient-derived organoids.
Main Results:
- R-P@APM-DPs demonstrated high R848 loading capacity (34.3%) and ROS-responsive release.
- The treatment significantly inhibited tumor growth in the MB49 model.
- Enhanced infiltration of CD8+ and CD4+ T cells and M1 macrophages, with a reduction in immunosuppressive cells, was observed.
Conclusions:
- The ROS-responsive prodrug R-P@APM-DPs effectively reshapes the tumor microenvironment and enhances anti-tumor immunity.
- Combination therapy with anti-PD-1 antibodies shows potent synergistic anti-cancer effects.
- This prodrug strategy holds significant translational potential for improving ICI-based immunotherapies in bladder cancer.
