Therapeutic Targeting of the IRF9/RTN4/RHOA/ROCK Pathway via RVG29-Modified PLGA Nanoparticles and rTMS for Neural and Vascular Regeneration Post-Cerebral Infarction

  • Adv Healthc Mater. 2026 Jan;15(2):e01846. doi: 10.1002/adhm.202501846.
Fangfang Zhang  1  2 ,  Weijin Shen  3 ,  Siting Zhong  4  5 ,  Kai Wen  6 ,  Hongxing Wang  7  8
Affiliations
  • 1. Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410000, China.
  • 2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, 410000, China.
  • 3. Department of Rehabilitation, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000, China.
  • 4. Department of Rehabilitation, Xiangya Hospital, Central South University, Jiangxi. (National Regional Center for Neurological Diseases), Nanchang, Jiangxi, 330038, China.
  • 5. Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330038, China.
  • 6. Department of Rehabilitation, Xiangya Changde Hospital, Changde, 415000, China.
  • 7. Department of Rehabilitation, Chongqing University Three Gorges Hospital，School of Medicine，Chongqing University, Chongqing, 404100, China.
  • 8. Xinjiang Key Laboratory of Neurological Disorder Research, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000, China.
PMID: 40968528 DOI: 10.1002/adhm.202501846
Abstract

Cerebral infarction, a leading cerebrovascular disease, often results in severe neurological impairments and high mortality. This study investigates a novel therapeutic approach involving small interfering RNA targeting Interferon Regulatory Factor 9 (si-IRF9) delivered by RVG29-functionalized poly(lactic-co-glycolic acid) nanoparticles (NPs) (RVG29-PNPs@si-IRF9), in combination with high-frequency repetitive transcranial magnetic stimulation (rTMS), in promoting post-stroke regeneration. Using a middle cerebral artery occlusion rat model and an in vitro oxygen-glucose deprivation/reoxygenation system, the regenerative efficacy of this combinatory therapy is evaluated on both neural and vascular recovery. Mechanistically, our results identify the IRF9/Reticulon 4 (RTN4)/Ras homolog family member A (RHOA)/Rho-associated coiled-coil containing protein kinase (ROCK) pathway as a key mediator, which is effectively inhibited by RVG29-PNPs@si-IRF9. This inhibition enhances neurogenesis and angiogenesis, particularly when combined with rTMS. Moreover, the NP system demonstrates excellent biocompatibility and targeted delivery, highlighting its potential as a therapeutic platform for stroke rehabilitation. These findings provide a new perspective on integrating nanotechnology and neuromodulation to facilitate functional recovery after cerebral infarction.

Keywords
RVG29‐modified PLGA nanoparticles; cerebral infarction; neural regeneration; si‐IRF9; transcranial magnetic stimulation; vascular regeneration.
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