Zona pellucida-inspired smart viral vectors: a biomimetic platform for multi-modal immune evasion and triple-stimuli responsive gene delivery.

Pre-existing immunity and off-target toxicity limit the clinical translation of adeno-associated virus (AAV) vectors. Herein, we present a Zona Pellucida-inspired Smart Viral Vector (ZP-SVV) platform as a biomimetic design hypothesis that repurposes the evolutionarily optimized architecture of ZP glycoproteins to engineer intelligent viral vector surfaces. The system integrates a self-assembling ZP glycoprotein coating-covalently crosslinked filamentous meshes formed via ZP-N/ZP-C domain polymerization, yielding a tunable glycan shield with defined inter-filament pores-with a triple-stimuli responsive architecture of protease-sensitive linkers, pH-gated histidine-rich domains, and redox-sensitive disulfide bonds that releases payload only after sequential triggering, and with multi-modal immune evasion that pairs dense glycan shielding with extracellular matrix mimicry to evade humoral and cellular immune surveillance while preserving receptor accessibility. This biomimetic design is intended to enhance safety and efficiency relative to conventional PEGylation or membrane-wrapping strategies, with theoretical modeling predicting potentially improved tumor accumulation and controlled intracellular release. Presented as a testable design framework rather than a validated therapy, the ZP-SVV platform offers a new paradigm for rational vector engineering in reproductive medicine and oncolytic virotherapy.