This hypothesis proposes engineering therapeutic antibodies with dual functionality: LDLR-binding domains for CNS penetration coupled to anti-inflammatory payloads targeting glial NF-κB signaling. The strategy leverages LDLR's well-characterized transcytotic properties at the blood-brain barrier to deliver antibodies that specifically suppress microglial and astrocytic inflammatory programs. Upon crossing the BBB via LDLR-mediated transport, these engineered antibodies would target key inflammatory mediators (such as TNF-α, IL-1β, or NF-κB pathway components) within activated glia. This approach addresses the fundamental challenge of neuroinflammation by combining reliable CNS delivery with targeted suppression of the glial inflammatory cascade that drives extracellular adenosine accumulation and downstream ADORA2A pathway activation. The dual-targeting design ensures that anti-inflammatory intervention occurs specifically within the CNS compartment where neuroinflammation originates, rather than relying on systemic anti-inflammatory approaches that may have limited brain penetration.

This hypothesis proposes engineering therapeutic antibodies with dual functionality: LDLR-binding domains for CNS penetration coupled to anti-inflammatory payloads targeting glial NF-κB signaling. The strategy leverages LDLR's well-characterized transcytotic properties at the blood-brain barrier to deliver antibodies that specifically suppress microglial and astrocytic inflammatory programs. Upon crossing the BBB via LDLR-mediated transport, these engineered antibodies would target key inflammatory mediators (such as TNF-α, IL-1β, or NF-κB pathway components) within activated glia. This approach addresses the fundamental challenge of neuroinflammation by combining reliable CNS delivery with targeted suppression of the glial inflammatory cascade that drives extracellular adenosine accumulation and downstream ADORA2A pathway activation. The dual-targeting design ensures that anti-inflammatory intervention occurs specifically within the CNS compartment where neuroinflammation originates, rather than relying on systemic anti-inflammatory approaches that may have limited brain penetration. By suppressing glial NF-κB signaling pathways that regulate ectonucleotidase expression and cytokine production, this strategy would reduce the sustained extracellular adenosine tone that contributes to mood circuit dysfunction. The LDLR transport mechanism provides quantifiable, consistent delivery that bypasses the variability inherent in FcRn-dependent transport, while the targeted anti-inflammatory payload addresses the upstream inflammatory processes that drive adenosinergic dysfunction in neuropsychiatric and neurodegenerative conditions.