IMMUNOMODULATORY DRUG DELIVERY SYSTEM FOR NEONATAL HYPOXIC ISCHEMIC ENCEPHALOPATHY
Date
2025-05
Authors
Journal Title
Journal ISSN
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Publisher
University of Delaware
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.