Spider venom: Reprogramming nature's peptide arsenal for future therapeutics

Background and purpose: Spider venom peptides are chemically diverse scaffolds with high potency, selectivity and structural stability, but native toxins often require optimization for therapeutic use. This review examines strategies for reprogramming spider venom peptides to improve selectivity, stability, safety and delivery. Experimental approach: Recent literature on venomics, sequence redesign, motif grafting, lipidation, terminal modification, peptidomimetic tuning, ligation and synthesis and delivery engineering was examined. Key results: Inhibitor cystine knot peptides provide robust scaffolds for ion-channel modulation, while linear peptides, enzymes and acylpolyamines broaden chemical space. Transcriptomics, proteomics, computational mining and machine learning accelerate discovery and functional prioritization. Rational substitutions, hybridization, lipidation, terminal editing, synthesis and nanocarrier engineering can improve pharmacological and developability profiles, although trade-offs remain. Conclusion: Spider venom research is moving from toxin discovery toward developability-focused reprogramming. Future progress requires integrated structural biology, medicinal chemistry, scalable synthesis and delivery science to address short half-life, off-target activity, manufacturability and venom scarcity.