Injectable Mechanophore\nNanoparticles for Deep-Tissue\nMechanochemical Dynamic Therapy

Photodynamic\ntherapy (PDT) and sonodynamic therapy (SDT),\nusing\nnonionizing light and ultrasound to generate reactive oxygen species,\noffer promising localized treatments for cancers. However, the effectiveness\nof PDT is hampered by inadequate tissue penetration, and SDT largely\nrelies on pyrolysis and sonoluminescence, which may cause tissue injury\nand imprecise targeting. To address these issues, we have proposed\na mechanochemical dynamic therapy (MDT) that uses free radicals generated\nfrom mechanophore-embedded polymers under mechanical stress to produce\nreactive oxygen species for cancer treatment. Yet, their application\nin vivo is constrained by the bulk form of the polymer and the need\nfor high ultrasound intensities for activation. In this study, we\ndeveloped injectable, nanoscale mechanophore particles with enhanced\nultrasound sensitivity by leveraging a core–shell structure\ncomprising silica nanoparticles (NPs) whose interfaces are linked\nto polymer brushes by an azo mechanophore moiety. Upon focused ultrasound\n(FUS) treatment, this injectable NP generates reactive oxygen species\n(ROS), demonstrating promising results in both an in vitro 4T1 cell\nmodel and an in vivo mouse model of orthotopic breast cancers. This\nresearch offers an alternative therapy technique, integrating force-responsive\nazo mechanophores and FUS under biocompatible conditions.