Cascade nanoreactor employs mitochondrial-directed chemodynamic and δ-ALA-mediated photodynamic synergy for deep-seated oral cancer therapy.

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. We introduced a cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment. Utilizing iron oxide nanoparticles and mesoporous silica, we developed the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA). Triphenylphosphine (TPP) modification facilitated mitochondrial targeting, while tumor cell membrane (TCM) coating provided homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM nanoparticles demonstrated efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggered δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria underwent Fenton chemistry for CDT. The synergistic interaction of PDT and CDT mechanisms increased cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic and damage mechanisms, ultimately leading to enhanced tumor cell death. PDT/CDT-induced apoptosis generated δ-ALA-containing apoptotic bodies, enhancing anti-tumor efficacy in deep tumor cells. The advantageous anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing systemic side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment. This article is protected by copyright. All rights reserved.