IMMUNOMODULATORY DRUG DELIVERY SYSTEM FOR NEONATAL HYPOXIC ISCHEMIC ENCEPHALOPATHY

Abstract

Occurring in 1.5 per 1000 live births, hypoxic ischemic encephalopathy (HIE) is a leading cause of death and long-term disability in children born at term. Interleukin-33 (IL-33), a nuclear cytokine released in response to injury, has emerged as a potent immunomodulator capable of reprogramming microglia toward a reparative phenotype. However, systemic IL-33 delivery can cause off-target effects, highlighting the need for localized therapeutic strategies. To address this, we developed an injectable alginate-based hydrogel system incorporating laponite nanoclay to enable tunable, intracranial delivery of IL-33. The hydrogel was engineered for optimal viscosity and release kinetics compatible with small-gauge needle injection into brain tissue. Using this platform, we evaluated microglial responses to IL-33 under control, Maternal Immune Activation (MIA), and HIE conditions in vitro. IL-33 treatment induced morphological changes consistent with a reparative (M2-like) phenotype and significantly enhanced phagocytic activity across all conditions, particularly rescuing deficits observed in HIE-exposed microglia. However, IL-33 did not significantly reduce pro-inflammatory cytokine levels (IL-1β, IL-6), suggesting its benefits may occur through phenotype modulation rather than direct cytokine suppression. These results demonstrate the potential of IL-33-loaded hydrogels as a targeted immunotherapeutic strategy for neonatal neuroinflammation.