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Ibdanelo Cortez,1,* Caitlyn M Gaffney,1,* Riddhi Vichare,2 Caitlin V Crelli,2 Lu Liu,2 Eric Lee,1 Jules Edralin,1 James M Nichols,1 Hoang Vu Pham,1 Syed Mehdi,1 Jelena M Janjic,2 Andrew J Shepherd1 1Laboratories of Neuroimmunology, Department of Symptom Research, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; 2School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA*These authors contributed equally to this workCorrespondence: Jelena M Janjic, School of Pharmacy, Duquesne University, 600 Forbes Ave., Pittsburgh, PA, 15282, USA, Email janjicj@duq.edu Andrew J Shepherd, Laboratories of Neuroimmunology, Department of Symptom Research, the University of Texas MD Anderson Cancer Center, Unit 1055, 6565 MD Anderson Boulevard, Houston, TX, 77030, USA, Tel +1 713 745-7959, Fax +1 832 750-5153, Email ajshepherd@mdanderson.orgAbstract: Soft tissue injuries often involve muscle and peripheral nerves and are qualitatively distinct from single-tissue injuries. Prior research suggests that damaged innervation compromises wound healing. To test this in a traumatic injury context, we developed a novel mouse model of nerve and lower limb polytrauma, which features greater pain hypersensitivity and more sustained macrophage infiltration than either injury in isolation. We also show that macrophages are crucial mediators of pain hypersensitivity in this model by delivering macrophage-targeted nanoemulsions laden with the cyclooxygenase-2 (COX-2) inhibitor celecoxib. This treatment was more effective in males than females, and more effective when delivered 3 days post-injury than 7 days post-injury. The COX-2 inhibiting nanoemulsion drove widespread anti-inflammatory changes in cytokine expression in polytrauma-affected peripheral nerves. Our data shed new light on the modulation of inflammation by injured nerve input and demonstrate macrophage-targeted nanoimmunomodulation can produce rapid and sustained pain relief following complex injuries. Keywords: nerve injury, muscle contusion, inflammation, celecoxib, nanoemulsion, COX-2