Pharmaceutical Strategies for Translating Klotho-Based Therapeutics: From Biologic Developability to Advanced Delivery Systems.

Klotho is a longevity-associated and tissue-protective protein involved in mineral metabolism, oxidative stress, inflammation, fibrosis, cellular senescence, and neurovascular homeostasis. However, nearly three decades after its discovery, no Klotho-based therapy has been approved, highlighting a translational gap that extends beyond biological validation. This review reframes Klotho translation as a pharmaceutical sciences challenge, focusing on how to convert Klotho into a druggable, manufacturable, deliverable, and clinically controllable therapeutic product. We summarize the isoform-specific properties of membrane-bound α-Klotho, soluble α-Klotho, and β-Klotho that are relevant to product design, and review the current clinical and preclinical landscape dominated by gene-, mRNA-, and antibody-based approaches. We further distinguish confirmed developability barriers, including renal handling and limited systemic persistence, from plausible risks common to macromolecular biologics, such as aggregation, chemical degradation, immunogenicity, and poor tissue penetration. Finally, we evaluate emerging delivery and formulation strategies, including viral and non-viral gene delivery, extracellular vesicles, hydrogels, ultrasound-targeted microbubbles, osmotic pumps, and long-acting protein engineering. An integrated roadmap combining molecular engineering, disease-specific delivery, pharmacokinetic/pharmacodynamic biomarkers, manufacturability assessment, and repeated-dose safety evaluation may help transform Klotho from a promising anti-aging molecule into a clinically viable biologic platform.