# Nanogel Integrated Zwitterionic Injectable Hydrogel with Sequential Drug‐Releasing Capability for the Programmable Repair of Spinal Cord Injury

## TL;DR

A new injectable hydrogel with sequential drug release is developed to improve spinal cord injury repair by combining anti-inflammatory and signaling pathway-blocking effects.

## Contribution

A novel nanogel-integrated hydrogel system enables programmable, sequential drug release for spinal cord injury repair.

## Key findings

- Melatonin is released first via diffusion, reducing inflammation in the acute phase of SCI.
- Ibuprofen is released later through electrostatic interactions, blocking the ROCK pathway in the subacute phase.
- The hydrogel platform shows excellent repair outcomes by combining anti-inflammatory and signaling pathway effects.

## Abstract

Spinal cord injury (SCI), a highly disabling injury to the central nervous system, has a complex and sequential pathogenesis. Traditional multiple‐delivery systems rely on a physical mix of nanoparticles or drugs in hydrogels, which lacks the controllability of the drug. To solve these problems, an integrative hydrogel system cross‐linked with a Per‐g‐PSB nanogel is designed. Dendritic macromolecular nanogels (Per‐g‐PSB) could not only act as cross‐linkers to adjust the hydrogel mechanical properties but also form a dynamic network (Dex/Per‐g‐PSB hydrogel). Most importantly, a large amount of charge could lead to a significant sustained release via electrostatic interactions. The hydrogel platform (Mel/Ibu@D/P‐g‐PSB) realizes the sequential release of melatonin and ibuprofen by different mechanisms. Melatonin is first released by diffusion and exhibits significant neuroprotective effects during the acute phase by downregulating the expression of inflammatory cytokines. Ibuprofen is released in the second stage due to strong electrostatic interactions, and it reduces RhoA signaling activation by blocking the ROCK pathway in the subacute phase, which reduces the deleterious cascade reaction after spinal cord injury. These results show that the ion‐sensitive hydrogel platform with sequentially releasing drug effects, combining anti‐inflammatory effects and blocking the ROCK pathway, shows excellent repair of SCI.

A novel drug‐loaded D/P‐g‐PSB nanogel‐incorporated hydrogel by the electrostatic attraction‐driven self‐assembling process. Sequential drug releasing property (melatonin is released first by physical diffusion, and then ibuprofen is released as the charge shielding effect and hydrogel degradation). This ion‐sensitive hydrogel platform with sequentially releasing drug effects, combining anti‐inflammatory effects and blocking the ROCK pathway, shows excellent repair of SCI.