Self-assembling 'spider peptide' P1 generates ROS in mitochondria, inhibiting glioma growth in mice

Treating brain glioma, a highly energy-dependent malignant tumor, remains challenging. While sonodynamic therapy (SDT) offers a noninvasive approach, its efficacy hinges on efficient delivery and localized generation of reactive oxygen species (ROS) from sonosensitizers. Current methods often struggle with precise ROS targeting within tumor cells, particularly at critical energy hubs like mitochondria. This study addresses the need for a targeted ROS delivery system to enhance SDT's impact on glioma's metabolic vulnerabilities.

Researchers constructed a self-assembling 'spider peptide' (P1) bearing porphyrin moieties, designed to generate ROS under ultrasound. They then loaded peptide P1 into glioma-derived exosomes (Evs@P1) to enhance blood-brain barrier (BBB) permeability and homotypic targeting. The Evs@P1 complexes were tested in glioma cells in vitro and subsequently in vivo in mice with brain glioma. The study evaluated P1's ability to self-assemble, target mitochondria, generate ROS under ultrasound, and inhibit glioma cell growth and tumor progression.

In glioma cells, P1 formed web-like nanofibers that specifically wove around mitochondria, enabling in situ ROS release. Glioma-derived exosomes loaded with P1 (Evs@P1) demonstrated enhanced blood-brain barrier permeability and effective homotypic targeting to glioma cells. After endocytic uptake, Evs@P1 complexes underwent hydrolysis in the acidic lysosomal environment, exposing the mitochondrial-targeting peptide. Ultrasound significantly enhanced the rate of peptide self-assembly into nanofibers, which were then extruded from the exosomes and localized around the mitochondrial surface. This assembly of P1 nanofibers accelerated ROS generation, leading to a substantial increase.

ROS generation was 3.7 times higher in the assembled nanofiber state compared to the monomeric state. This efficient ROS production effectively disrupted the energy metabolism of mitochondria, leading to significant inhibition of glioma cell growth in vitro and demonstrating an effective method to prevent glioma growth in mice brains in vivo.