Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury

Mayilsamy, K.; Patel, P. B.; Green, R.; Bikkasani, S.; Tosi, K.; Majumdar, S.; Prajapati, S.; Markoutsa, E.; Wolf, T.; Guergues, J.; Stevens, S. M.; Willing, A.; Mohapatra, S.

doi:10.64898/2026.09.04.748639

bioRxiv · 10.64898/2026.09.04.748639

Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury

Mayilsamy, K.·Patel, P. B.·Green, R.·Bikkasani, S.·Tosi, K.·Majumdar, S.·Prajapati, S.·Markoutsa, E.·Wolf, T.·Guergues, J.·Stevens, S. M.·Willing, A.·Mohapatra, S.

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Abstract

Repetitive traumatic brain injury (rTBI) induces persistent microglial activation and chronic neuroinflammation, yet the upstream signals driving long-term synaptic injury remain unclear. In this study, we identify the CCL20-CCR6 chemokine axis as a critical regulator of sustained microglial activation and complement-dependent synaptic loss after rTBI. Proteomic profiling at 30 days post-injury (dpi) showed broad normalization of complement-linked inflammatory and synaptic pathways in the cortex and hippocampus, underscoring a mechanistic link between chemokine signaling, microglial activation, and synaptic vulnerability. To therapeutically target this axis, we developed a dendrimer-based shRNA platform (shCombo-DPX) that simultaneously silences CCL20 and CCR6. Intranasal and intravenous delivery in rTBI mice effectively reduced CCL20-CCR6 expression, attenuated chronic microgliosis and astrogliosis, and suppressed complement activation. Treatment limited microglial synaptic engulfment, preserved synaptic proteins, restored BDNF levels, and improved motor, anxiety-related, and cognitive outcomes. In microglia-neuron coculture systems, CCL20 silencing reduced LPS-induced complement signaling and prevented synaptic loss, neuronal apoptosis, and BDNF depletion. Conversely, exposure to recombinant CCL20 induced dendritic degeneration, caspase-3 activation, microglial reactivity, complement dysregulation, and synaptic injury both in vitro and in vivo. Collectively, these findings establish CCL20-CCR6 as a key upstream driver of chronic complement-mediated synaptic degeneration after rTBI and support dendrimer-delivered shRNA therapy as a targeted strategy to mitigate long-term neurodegeneration.

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Mayilsamy, K., Patel, P. B., Green, R., Bikkasani, S., Tosi, K., Majumdar, S., Prajapati, S., Markoutsa, E., Wolf, T., Guergues, J., Stevens, S. M., Willing, A., Mohapatra, S.. 2026-09-09. Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury. https://doi.org/10.64898/2026.09.04.748639

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