A Coupling-Induced Assembly Strategy for Constructing Artificial Shell on Mitochondria in Living Cells

Area of Science:

• Biomaterials Science
• Nanotechnology
• Cancer Therapy

Background:

• In vivo self-assembly strategies aim to improve anticancer drug retention in tumors.
• Non-covalently bonded self-assemblies often lack stability in physiological environments, compromising function.
• Mitochondria are key targets for enhancing cancer therapy due to their role in cell death.

Purpose of the Study:

• To develop a stable, covalently crosslinked nanofiber system for targeted anticancer drug delivery.
• To create an artificial mitochondrial shell using a coupling-induced assembly (CIA) strategy.
• To enhance sonodynamic therapy (SDT) by leveraging mitochondria-targeted reactive oxygen species (ROS) generation.

Main Methods:

• Synthesis of an oxidation-responsive peptide-porphyrin conjugate (P1) that self-assembles into nanoparticles.
• Utilizing the oxidative mitochondrial microenvironment to induce thiol coupling and form crosslinked nanofibers.
• Constructing an artificial shell on mitochondria via multivalent cooperative interactions.

Main Results:

• The CIA strategy successfully generated covalently crosslinked nanofibers on mitochondria.
• The artificial mitochondrial shell efficiently increased binding sites and stability.
• Ultrasound irradiation of the shell produced ROS, leading to approximately a 2-fold increase in antitumor activity in vitro and in vivo compared to nanoparticles.

Conclusions:

• The mitochondria-targeted CIA strategy offers a novel approach for stable drug delivery systems.
• This method significantly enhances sonodynamic therapy efficacy through localized ROS production.
• The developed strategy shows promising potential for advanced antitumor therapies.