Inflammatory Microenvironment‐Responsive Nanomaterials Promote Spinal Cord Injury Repair by Targeting IRF5

Abstract

Spinal cord injury (SCI) involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages rather than prohealing M2 macrophages, and oxidative stress. Interferon regulatory factor 5 (IRF5) is a promising therapeutic target in regulation of macrophage reprogramming from the M1 to M2 phenotype. However, knockdown of IRF5 expression mediated by small interfering RNA (siRNA) is limited by instability and poor cellular uptake. In the present study, polyethylenimine‐conjugated, diselenide‐bridged mesoporous silica nanoparticles are tailored to regulate macrophage polarization by controllably delivering siRNA to silence IRF5. The MSN provides reactive oxygen species (ROS)‐responsive degradation and release, while polyethylenimine‐function offers efficient loading of siRNA‐IRF5 and enhanced endosome escape. As a consequence, the intelligent nanomaterial effectively transfects the siRNA‐IRF5 with its remaining high stability and bioactivity, thereby effectively regulating the M1‐to‐M2 macrophage conversion in vitro and in vivo. Importantly, administration of the functional nanomaterial in crush SCI mice suppresses excessive inflammation, enhances neuroprotection, and promotes locomotor restoration. Collectively, the ROS‐responsive nanomedicine provides a gene silencing strategy for regulating macrophage polarization and oxidative balance in SCI repair.

Mesoporous Silica-Based Nanoplatforms Are Theranostic Agents for the Treatment of Inflammatory Disorders

“…ROS-responsive MSN-SiRNA inhibited the synthesis of TNF-α, IL-6, and iNOS, enhancing the anti-inflammatory cytokine (IL-10) in the SCI lesion. Thus, the ROS-responsive MSN improves the intracellular transfection rate, regulates the M1 and M2 macrophage transition, supports the anti-inflammatory responses, and promotes the neural protection and functional recovery of SCI mice [ 120 ].…”

Biomaterial‐Based Gene Delivery to Central Nervous System Cells for the Treatment of Spinal Cord Injury

“…IRF5 is a key transcription factor involved in the regulation of macrophage phenotype (and master regulator of macrophage polarization) [166] and downregulation also skews the polarization of the cells to the anti-inflammatory M2 phenotype. Studies that knocked down IRF5 function in the injured cord, using bone marrow-derived MSC exosomes loaded with microRNA to IRF5 (miR-IRF5 [167] ), lipidoid-loaded siRNA, [168] or silica-loaded siRNA, [169] promoted the polarization of macrophages toward the proreparative M2-phenotype [167][168][169] and was associated with tissue sparing and improvement in locomotor function in a mouse model of contusion injury. [168] Similarly, exosomes encapsulating siRNA to connective tissue growth factor (CTGF) also boosted mRNA expression of M2 macrophage markers and reduced glial scar formation in the contused rat cord.…”

Reactive oxygen species targeted biomaterials for spinal cord injury therapy

“…Ma et al. created a ROS‐responsive biomaterial platform using mesoporous silica nanoparticles that contained diselenide bonds and PEI [41] . Using CellROX Green to assess macrophage ROS levels established the intrinsic capacity of this nanoplatform to manage intracellular ROS levels.…”

“…From a combination therapy perspective, [2,17,[65][66][67] enzymatic biomaterials currently demonstrate limitations in effectively synergizing with other treatment modalities, and further exploration of this challenge is needed in the context of SCI. Nonenzymatic biomaterials, including both inorganic and organic core types, are commonly paired with cell therapy, [35,45,49,65,68,69] protein therapy, [46,68,70,71] neuromodulation therapy, [2,51,72] or gene regulation therapy [41,73] for SCI treatment. Combination therapy approaches appear essential for achieving the ultimate goal of SCI repair.…”

“…Ma et al created a ROS-responsive biomaterial platform using mesoporous silica nanoparticles that contained diselenide bonds and PEI. [41] Using CellROX Green to assess macrophage ROS levels established the intrinsic capacity of this nanoplatform to manage intracellular ROS levels. Subsequent to proficient siRNA-IRF5 transfection and adept ROS modulation, the nanomaterials effectively orchestrated the conversion of macrophages from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype.…”