National Institutes of Biotechnology Malaysia

The COVID-19 pandemic elicited by SARS-CoV-2 has led to a world-wide crisis, affecting a substantial percentage of the entire global population, and has engendered profound morbidity and fatalities. SARS-CoV-2 mediates its entry into human respiratory epithelial cells via interaction between viral Spike protein (S) and ACE2 receptor and enacts the host cell tropism by numerous molecular factors and inflammatory signaling pathways. The complex molecular immunopathogenesis involves loss of regulatory control of the generation & release of proinflammatory cytokines at both local as well as systemic levels. Excessive secretion of pro-inflammatory cytokines and chemokines leads to the dysregulation of the innate immune system leading to the cytokine storm. Owing to the enormous release of inflammatory factors and active mediators, cytokine storm induces severe damage to secondary tissues, leading to Acute Respiratory Distress Syndrome (ARDS) or multiple-organ failure, which evokes aggravation of the disease and eventually death. Comparisons amid COVID-19 cytokine storm and several other types of cytokine storm associated diseases, gives proper insights about the etiology of cytokine storm in COVID-19. Various genetic and physiological factors contribute to severe disease progression and aggravation of the disease. In that view, several immunoregulatory therapies have been tailored to curb the cytokine storm, which might be crucial in improving the success rates of various treatment strategies as well as in lowering the mortality rate in COVID-19 patients. This review elucidates the hallmarks of COVID-19 cytokine storm, immunopathogenesis, disease progression, biomarkers, and therapeutic interventions.

Autoimmune diseases are driven by dysregulated cytokine networks, where excessive cytokines such as TNF-α, IL-6, IL-17, and IL-23 promote chronic inflammation and tissue damage. While monoclonal antibodies effectively neutralise these cytokines, they face limitations including high production costs, glycosylation requirements, limited tissue penetration, and immunogenicity. Nanobodies; small, single-domain antibodies derived from camelids, offer a promising alternative due to their high stability, solubility, microbial expression, and low immunogenicity. This review examines the structural and functional advantages of nanobodies in cytokine neutralisation, with targets including TNF-α, IL-6, IL-17 A, chemokines (e.g., CXCL10), VEGF, and intracellular proteins like STAT3. Advances in artificial intelligence (AI) and machine learning (ML) for nanobody discovery, from de novo library design to affinity optimization, are highlighted. We also discuss Chemistry, Manufacturing, and Controls (CMC), regulatory pathways (FDA/EMA), and innovative delivery strategies such as oral and nanoparticle systems. Furthermore, the advantages and limitations of nanobody-based cytokine neutralisation are critically evaluated. Lastly, we review the current status of clinical trials and future directions to enhance efficacy and safety of nanobody-based therapies in autoimmune diseases.