Injectable hydrogel-mediated spermidine delivery triggers tumor pyroptosis via oxidative metabolism for enhanced
Zheng Deng1, Xirui Wu2, Tianhao Huang2
1The Fourth Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China; Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China.
Abstract:
Intracellular polyamine metabolic homeostasis is closely linked to therapeutic outcomes in cancer. However, their intrinsic antitumor mechanisms have not been fully clarified. Herein, we demonstrate that the catabolism of spermine (Spm) and spermidine (Spd) mediated by polyamine oxidase directly generates two potent cytotoxic metabolites, namely acrolein and hydrogen peroxide. These metabolites act synergistically to trigger a marked elevation in intracellular reactive oxygen species (ROS), which in turn activate the caspase-1/GSDMD and caspase-3/GSDME signaling pathways, ultimately driving tumor cells into pyroptosis. Based on these findings, we develop a phenylboronic acid-functionalized sodium alginate-based hydrogel controlled-release system (Alg-PBA/Spd). This platform achieves sustained Spd release through coordination interactions and markedly inhibits tumor growth by inducing pyroptosis. Further studies demonstrate that the Alg-PBA/Spd hydrogel synergizes with radiotherapy (RT) to enhance radiosensitivity in an orthotopic breast cancer model and inhibit pulmonary metastasis. Moreover, this hydrogel enables co-delivery of αPD-L1 with sustained release, which significantly improves the response rate of immune checkpoint blockade therapy by inducing pyroptosis and remodeling the tumor immune microenvironment. Overall, this study not only elucidates a previously unrecognized mechanism underlying polyamine metabolism-driven pyroptosis but also offers a versatile platform to enhance the efficacy of RT and immunotherapy.
Insights
Polyamines like spermine and spermidine can kill cancer cells by producing toxic byproducts that trigger cell death. A new hydrogel system delivers spermidine to induce pyroptosis, enhancing cancer therapy.
Area of Science:
- Biochemistry
- Cancer Biology
- Materials Science
Background:
- Intracellular polyamine metabolism is crucial for cancer treatment outcomes.
- The precise antitumor mechanisms of polyamines remain incompletely understood.
Purpose of the Study:
- To elucidate the antitumor mechanisms of polyamine catabolism.
- To develop a novel drug delivery system for enhanced cancer therapy.
Main Methods:
- Investigated the cytotoxic effects of spermine and spermidine catabolism.
- Developed a phenylboronic acid-functionalized sodium alginate hydrogel for controlled spermidine release (Alg-PBA/Spd).
- Evaluated the hydrogel's efficacy alone and in combination with radiotherapy and immunotherapy in preclinical cancer models.
Main Results:
- Spermine and spermidine catabolism generates cytotoxic acrolein and hydrogen peroxide, inducing reactive oxygen species (ROS).
- ROS activates caspase-1/GSDMD and caspase-3/GSDME pathways, leading to tumor cell pyroptosis.
- The Alg-PBA/Spd hydrogel effectively inhibited tumor growth by inducing pyroptosis.
- The hydrogel enhanced radiotherapy efficacy, reduced metastasis, and improved immunotherapy response by remodeling the tumor immune microenvironment.
Conclusions:
- Polyamine metabolism-driven pyroptosis is a novel antitumor mechanism.
- The Alg-PBA/Spd hydrogel is a versatile platform for enhancing cancer treatment by inducing pyroptosis and supporting combination therapies.
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