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Purpose <p>This review critically evaluates the dual role of proprotein convertase subtilisin/kexin type 9 (PCSK9) beyond cholesterol homeostasis, specifically examining its involvement in viral pathogenesis, and assesses the potential of nanoparticle (NP)-based delivery systems&#xa0;to overcome translational barriers for PCSK9-targeted therapies in viral infections.</p> Methods <p>A comprehensive literature search was conducted in PubMed, Google Scholar, and ClinicalTrials.gov (2008-2026) using keywords including PCSK9 inhibition, nanoparticles, lipid metabolism, nanomedicine, viral infections, and clinical challenges. Peer-reviewed original research, clinical trials, systematic reviews, and regulatory guidelines were included. comprehensive literature search was conducted in PubMed, Google Scholar, and ClinicalTrials.gov (2008-2026) using keywords including PCSK9 inhibition, nanoparticles, lipid metabolism, nanomedicine, viral infections, and clinical challenges. Peer-reviewed original research, clinical trials, systematic reviews, and regulatory guidelines were included.</p> Results <p>PCSK9 modulates viral pathogenesis through virus-specific mechanisms: antiviral effects (hepatitis C virus (HCV), vesicular stomatitis virus (VSV), influenza via LDLR/CD81 degradation and mitochondrial antiviral-signaling protein (MAVS) stabilization) versus proviral effects (dengue virus (DENV), severe COVID-19 via SREBP-2 activation and type I interferon suppression). Approved PCSK9 inhibitors demonstrate robust LDL-C reduction (50-70%) but face significant translational hurdles for antiviral applications, including suboptimal biodistribution, lack of cell-specific targeting, high costs, and potential off-target effects on LDLR family members. NP-based delivery systems address these limitations by enhancing bioavailability, enabling cell-specific targeting, such as hepatocyte-directed delivery, facilitating controlled release, supporting combination therapy approaches, and mitigating systemic adverse effects. Emerging platforms also enable concurrent delivery of PCSK9-targeted agents and immunomodulators, opening avenues for combinatorial antiviral strategies.</p> Conclusion <p>PCSK9 represents a promising host-directed therapeutic target in viral infections, particularly for DENV and severe COVID-19 where it exerts proviral effects. NP-based delivery systems offer transformative solutions to current translational barriers through improved targeting, controlled modulation, and reduced off-target toxicity. Successful clinical translation will require addressing regulatory considerations, manufacturing scalability, long-term safety monitoring, and indication-specific clinical trial designs tailored to viral pathogenesis.</p> Graphical Abstract <p></p>

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Nanoparticle-Based PCSK9 Inhibition in Viral Infections: Evaluating Clinical Limitations and Advancing Therapeutic Strategies

  • 期刊论文

  • 发表日期：

    2026年4月21日

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  • Moeen Fuad Dababneh,
  • Bahjat Alhasso,
  • Abdulkareem Shareef,
  • Ashishkumar Kyada,
  • H. Malathi,
  • Laxmidhar Maharana,
  • Dinesh Puri,
  • Harshit Gupta,
  • Nargiza Yarmukhamedova,
  • Hayder Naji Sameer,
  • Ahmed Yaseen,
  • Zainab H. Athab,
  • Mohaned Adil

摘要

Purpose

This review critically evaluates the dual role of proprotein convertase subtilisin/kexin type 9 (PCSK9) beyond cholesterol homeostasis, specifically examining its involvement in viral pathogenesis, and assesses the potential of nanoparticle (NP)-based delivery systems to overcome translational barriers for PCSK9-targeted therapies in viral infections.

Methods

A comprehensive literature search was conducted in PubMed, Google Scholar, and ClinicalTrials.gov (2008-2026) using keywords including PCSK9 inhibition, nanoparticles, lipid metabolism, nanomedicine, viral infections, and clinical challenges. Peer-reviewed original research, clinical trials, systematic reviews, and regulatory guidelines were included. comprehensive literature search was conducted in PubMed, Google Scholar, and ClinicalTrials.gov (2008-2026) using keywords including PCSK9 inhibition, nanoparticles, lipid metabolism, nanomedicine, viral infections, and clinical challenges. Peer-reviewed original research, clinical trials, systematic reviews, and regulatory guidelines were included.

Results

PCSK9 modulates viral pathogenesis through virus-specific mechanisms: antiviral effects (hepatitis C virus (HCV), vesicular stomatitis virus (VSV), influenza via LDLR/CD81 degradation and mitochondrial antiviral-signaling protein (MAVS) stabilization) versus proviral effects (dengue virus (DENV), severe COVID-19 via SREBP-2 activation and type I interferon suppression). Approved PCSK9 inhibitors demonstrate robust LDL-C reduction (50-70%) but face significant translational hurdles for antiviral applications, including suboptimal biodistribution, lack of cell-specific targeting, high costs, and potential off-target effects on LDLR family members. NP-based delivery systems address these limitations by enhancing bioavailability, enabling cell-specific targeting, such as hepatocyte-directed delivery, facilitating controlled release, supporting combination therapy approaches, and mitigating systemic adverse effects. Emerging platforms also enable concurrent delivery of PCSK9-targeted agents and immunomodulators, opening avenues for combinatorial antiviral strategies.

Conclusion

PCSK9 represents a promising host-directed therapeutic target in viral infections, particularly for DENV and severe COVID-19 where it exerts proviral effects. NP-based delivery systems offer transformative solutions to current translational barriers through improved targeting, controlled modulation, and reduced off-target toxicity. Successful clinical translation will require addressing regulatory considerations, manufacturing scalability, long-term safety monitoring, and indication-specific clinical trial designs tailored to viral pathogenesis.

Graphical Abstract