Nanoparticles (NPs) offer promising potential as therapeutic agents for inflammation-related diseases, owing to their capabilities in drug delivery and immune modulation. In preclinical studies focusing on spinal cord injury (SCI), polymeric NPs have demonstrated the ability to reprogram innate immune cells. This reprogramming results in redirecting immune cells away from the injury site, downregulating pro-inflammatory signaling, and promoting a regenerative environment post-injury. However, to fully understand the mechanisms driving these effects and maximize therapeutic efficacy, it is crucial to assess NP interactions with innate immune cells. This review examines how the physicochemical properties of polymeric NPs influence their modulation of the immune system. To achieve this, the review delves into the roles played by innate immune cells in SCI and investigates how various NP properties influence cellular interactions and subsequent immune modulation. Key NP properties such as size, surface charge, molecular weight, shape/morphology, surface functionalization, and polymer composition are thoroughly examined. Furthermore, the review establishes connections between these properties and their effects on the immunomodulatory functions of NPs. Ultimately, this review suggests that leveraging NPs and their physicochemical properties could serve as a promising therapeutic strategy for treating SCI and potentially other inflammatory diseases.