A novel ultrasound-responsive cluster bomb system for efficient siRNA delivery in brain.

in Ultrasonics sonochemistry by Tianyu Guo, Feihong Dong, Jingyi Yin, Xinnan Wang, Pengting Min, Jiabin Zhang, Heping Cheng, Jue Zhang

TLDR

  • Researchers develop an ultrasound-responsive siRNA delivery carrier that demonstrates significant improvements in drug delivery efficiency and safety for gene therapy in the brain.
  • The carrier offers a promising solution for brain tumors and neurodegenerative diseases by safely and reversibly opening the blood-brain barrier.

Abstract

RNA-based therapeutics using RNA interference have become a research hotspot for brain tumors and neurodegenerative diseases with the advancement of nanocarrier delivery technology. However, even with specific modifications, RNA-loaded nanoparticles face significant challenges in effectively crossing the blood-brain barrier (BBB) to achieve precise delivery of therapeutic agents to the brain. Focused ultrasound combined with microbubbles and nanodroplets has emerged as a promising approach for temporarily opening the BBB. However, the low drug loading capacity and fixed stimulation focus of these methods limit their integration with current nano-drug delivery systems. Herein, we introduced a fluorinated surfactant and developed an ultrasound-responsive siRNA delivery carrier that contains nanodroplets loaded with siRNA-carrying nanoparticles (siRNA@NP@ND), termed as "ultrasound-responsive 'cluster bomb' nanoplatform". Under precise and flexible guidance and stimulation through a programmable diagnostic ultrasound, siRNA@NP@ND demonstrated over a seventy-fold increase in efficiency for delivering siRNA to the mouse brain. Additionally, Evans blue staining and hematological analysis indicated that ultrasound-triggered cavitation could reversibly open the BBB for up to 48 h without causing significant immune or inflammatory responses. The minor intracranial hemorrhage resulting from this process was also shown to be recoverable. Our research provides an advanced and controllable delivery platform for gene therapy of intracranial central nervous system diseases.

Overview

  • The study explores the development of an ultrasound-responsive siRNA delivery carrier for targeted gene therapy in the brain, overcoming the challenges of the blood-brain barrier (BBB).
  • The researchers introduce a fluorinated surfactant and create an 'ultrasound-responsive 'cluster bomb' nanoplatform' that combines nanodroplets loaded with siRNA-carrying nanoparticles (siRNA@NP@ND).
  • The nanoplatform demonstrates a seventy-fold increase in siRNA delivery efficiency to the mouse brain under precise and flexible ultrasound guidance and stimulation.

Comparative Analysis & Findings

  • The study compares the performance of the ultrasound-responsive siRNA delivery carrier with existing methods, showing significant improvements in drug loading capacity and focused stimulation.
  • The carrier demonstrates a safe and reversible opening of the BBB, allowing for up to 48 hours of drug delivery without inducing significant immune or inflammatory responses.
  • The study also reports minor intracranial hemorrhage as a result of ultrasound-triggered cavitation, which was shown to be recoverable.

Implications and Future Directions

  • The research provides an advanced and controllable delivery platform for gene therapy of central nervous system diseases, offering a promising solution for brain tumors and neurodegenerative diseases.
  • Future studies can focus on scaling up the production of the nanoplatform and exploring its potential in human clinical trials.
  • The development of more sophisticated ultrasound systems and targeted diagnosis can further optimize the delivery of therapeutic agents to specific areas of the brain.
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