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Peer-reviewedCC BY-NC 4.0Materials Today Bio

pH/ROS dual-responsive SmartGel-Cas9/TRPV4 for autophagy regulation in intervertebral disc degeneration

  • Xiao-Jun Yu1,2
  • Bing-Yao Quan1,2
  • Peng Zou1,2
  • Si-Bo Wang1,2
  • Ling-Jiang Li1,2
  • Rongjin Luo1,2
  • Yong-Yuan Zhang1,2
  • Yuan-Ting Zhao1,2
  1. 1Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710054, China
  2. 2Shaanxi Key Laboratory of Spine Bionic Treatment, Xi'an, Shaanxi, China
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Abstract

This study developed a pH/ROS dual-responsive SmartGel platform for local CRISPR-Cas9 RNP delivery and TRPV4 inhibition in intervertebral disc degeneration (IVDD). The GelMA/PBA-based SmartGel responded to acidic and oxidative microenvironmental cues and released Cas9/sgRNA under disease-mimicking conditions. In nucleus pulposus (NP) cells, SmartGel-Cas9/TRPV4 lowered ROS accumulation, restored mitochondrial membrane potential (ΔΨm), and coordinated apoptosis, senescence, Ca2+ homeostasis, CaMKKβ-dependent AMPK-mTOR signaling, and autophagic flux. CaMKKβ knockdown weakened AMPK activation and mTOR inhibition and autophagic-flux restoration, supporting CaMKKβ as a required link in this mechanism. In the rat IVDD model, the system preserved disc architecture, improved hydration status, reinforced extracellular matrix (ECM) homeostasis, and restrained downstream pathological signaling. Exploratory scRNA-seq and proteomic analyses further indicated treatment-associated shifts in Ca2+/autophagy/MAPK/Wnt-related programs. Overall, SmartGel-Cas9/TRPV4 may attenuate IVDD by restoring CaMKKβ-associated autophagic degradation and ECM balance while limiting aberrant signaling activation.

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Cite

BibTeXRIS
BibTeX
@article{yu2026phros,
  title = {{pH/ROS dual-responsive SmartGel-Cas9/TRPV4 for autophagy regulation in intervertebral disc degeneration}},
  author = {Xiao-Jun Yu and Bing-Yao Quan and Peng Zou and Si-Bo Wang and Ling-Jiang Li and Rongjin Luo and Yong-Yuan Zhang and Yuan-Ting Zhao},
  journal = {Materials Today Bio},
  year = {2026},
  month = oct,
  doi = {10.1016/j.mtbio.2026.103768},
  url = {https://doi.org/10.1016/j.mtbio.2026.103768},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - pH/ROS dual-responsive SmartGel-Cas9/TRPV4 for autophagy regulation in intervertebral disc degeneration
AU  - Xiao-Jun Yu
AU  - Bing-Yao Quan
AU  - Peng Zou
AU  - Si-Bo Wang
AU  - Ling-Jiang Li
AU  - Rongjin Luo
AU  - Yong-Yuan Zhang
AU  - Yuan-Ting Zhao
PY  - 2026
DA  - 2026/10/20
JO  - Materials Today Bio
DO  - 10.1016/j.mtbio.2026.103768
UR  - https://doi.org/10.1016/j.mtbio.2026.103768
AB  - This study developed a pH/ROS dual-responsive SmartGel platform for local CRISPR-Cas9 RNP delivery and TRPV4 inhibition in intervertebral disc degeneration (IVDD). The GelMA/PBA-based SmartGel responded to acidic and oxidative microenvironmental cues and released Cas9/sgRNA under disease-mimicking conditions. In nucleus pulposus (NP) cells, SmartGel-Cas9/TRPV4 lowered ROS accumulation, restored mitochondrial membrane potential (ΔΨm), and coordinated apoptosis, senescence, Ca2+ homeostasis, CaMKKβ-dependent AMPK-mTOR signaling, and autophagic flux. CaMKKβ knockdown weakened AMPK activation and mTOR inhibition and autophagic-flux restoration, supporting CaMKKβ as a required link in this mechanism. In the rat IVDD model, the system preserved disc architecture, improved hydration status, reinforced extracellular matrix (ECM) homeostasis, and restrained downstream pathological signaling. Exploratory scRNA-seq and proteomic analyses further indicated treatment-associated shifts in Ca2+/autophagy/MAPK/Wnt-related programs. Overall, SmartGel-Cas9/TRPV4 may attenuate IVDD by restoring CaMKKβ-associated autophagic degradation and ECM balance while limiting aberrant signaling activation.
SN  - 2590-0064
ER  -