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Updated: May 5, 2026
Porous Silicon Microparticles for Delivery of siRNA Therapeutics
Published on: January 15, 2015
Sustained Release of HIF-2α Inhibitors Using Biodegradable Porous Silicon Carriers for Enhanced Immunogenic Cell
Juyoung Seong1,2, Minju Kim1, Jounghyun Yoo1
1Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
Abstract:
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with limited treatment options, often associated with Merkel cell polyomavirus (MCPyV) and marked by hypoxic tumor microenvironments that promote resistance to therapies. Belzutifan, an FDA-approved hypoxia-inducible factor-2α (HIF-2α) inhibitor, has shown promise in inhibiting tumor growth; however, its clinical efficacy is hindered by its low solubility, rapid clearance, and limited bioavailability. In this study, we present a strategy using porous silicon (pSi) microparticles and nanoparticles as carriers for the sustained delivery of benzoate to MCC cells. The pSi carriers were engineered to securely encapsulate and gradually release belzutifan, overcoming the limitations of free drug administration. Microparticles provided sustained extracellular release, while nanoparticles enabled efficient intracellular delivery, enhancing HIF-2α inhibition. Moreover, the use of biodegradable silicon particles enables long-term consistent release of belzutifan over 10 days in vitro with a single dose administration in the tumor microenvironment, while free belzutifan is rapidly deactivated within 1 day postadministration. In vitro studies demonstrated significant immunogenic cell death (ICD) in MCC cells, marked by the cytosolic localization of HMGB1 and elevated expression of pro-inflammatory cytokines as well as strong upregulation of TLR9. Particularly, the increased TLR9 expression in both MCC cell lines with pSi carrier treatment reinforces immune activation through toll-like receptor signaling, enhancing both innate and adaptive immune responses within the tumor microenvironment. These findings indicate that pSi carriers not only enhance belzutifan's stability and release profile but also amplify antitumor immune responses within the tumor microenvironment. Our results suggest that belzutifan-loaded pSi carriers offer a potent and targeted therapeutic strategy for MCC, potentially addressing key challenges in cancer immunotherapy by combining HIF-2α inhibition with robust immune activation. This platform highlights the universal utility of pSi-based delivery systems to advance MCC treatment with implications for broader cancer therapies.
Insights
Porous silicon carriers enhance belzutifan delivery for Merkel cell carcinoma (MCC), improving drug efficacy and stimulating anti-tumor immune responses. This novel approach offers sustained drug release and better treatment outcomes for this rare skin cancer.
Area of Science:
- Biomaterials Science
- Cancer Biology
- Immunology
Background:
- Merkel cell carcinoma (MCC) is an aggressive skin cancer with limited treatment options.
- Hypoxic tumor microenvironments in MCC contribute to therapeutic resistance.
- Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, shows anti-tumor potential but faces bioavailability challenges.
Purpose of the Study:
- To develop a sustained drug delivery system for belzutifan using porous silicon (pSi) carriers for MCC treatment.
- To evaluate the efficacy of pSi-encapsulated belzutifan in enhancing HIF-2α inhibition and promoting immunogenic cell death (ICD) in MCC.
- To assess the impact of pSi carriers on immune activation within the tumor microenvironment.
Main Methods:
- Engineered porous silicon (pSi) microparticles and nanoparticles to encapsulate and control the release of belzutifan.
- Conducted in vitro studies to assess drug release kinetics, intracellular delivery, and HIF-2α inhibition.
- Evaluated MCC cell response, including immunogenic cell death markers (HMGB1, cytokines) and Toll-like receptor 9 (TLR9) expression.
Main Results:
- pSi carriers enabled sustained release of belzutifan over 10 days in vitro, contrasting with rapid deactivation of free belzutifan within 1 day.
- Nanoparticle carriers facilitated efficient intracellular drug delivery, enhancing HIF-2α inhibition.
- Treatment induced significant immunogenic cell death in MCC cells, characterized by increased pro-inflammatory cytokines and robust TLR9 upregulation, indicating enhanced immune activation.
Conclusions:
- Belzutifan-loaded pSi carriers provide a stable and effective drug delivery platform for MCC, overcoming limitations of free drug administration.
- This strategy enhances belzutifan's therapeutic potential by improving its pharmacokinetic profile and amplifying anti-tumor immune responses.
- Porous silicon-based delivery systems represent a promising therapeutic strategy for MCC, with potential applications in broader cancer immunotherapy by combining targeted drug delivery with immune stimulation.
