Transferrin-phosphatidylserine liposomes target TDP-43 and neuroinflammation in male mice with neuropathic pain.

Neuropathic pain (NP) is a debilitating condition driven by chronic neuroinflammation, where abnormal communication between microglia and astrocytes amplifies pain signaling. Current therapies offer limited benefit and primarily address symptoms rather than underlying mechanisms. Here, we show that transferrin- and phosphatidylserine-modified liposomes carrying a TDP-43 aggregation inhibitor (TF/PS/TDP-43-IN-1) effectively cross the blood-brain barrier, target glial cells, and modulate their activation states. In vitro, the formulation improved cell viability and promoted anti-inflammatory phenotypes. In vivo, studies conducted in male C57BL/6 J mice demonstrated significant alleviation of pain behaviors, reduced inflammatory cytokine expression, and suppression of the cGAS-STING pathway. These findings indicate that targeting TDP-43 aggregation with a nanocarrier system can reprogram glial interactions to relieve neuropathic pain. This strategy highlights a promising approach for developing targeted, disease-modifying therapies that act on key drivers of neuroinflammation.