238 / 2024-08-19 16:08:33

Albumins constrainting the conformation of mitochondria-targeted photosensitizers for tumor-specific photodynamic therapy

Photosensitizer,Mitochondria-targeted,Two-stage assembly,Phototherapy,Tumor ablation

Preclinical organelle-targeted phototherapies have effectively achieved tumor photoablation for regenerative biomedical applications in cancer therapies. However, engineering effective phototherapy drugs with precise tumor-localization targeting and organelle direction remains challenging. Herein, we propose a bovine serum albumin (BSA) constrainting mitochondrial-targeted photosensitizer (pyridocyanine) nanoparticles (PSs@BSAs) based on two-stage assembled engineering (TASE) strategy without the assistance of redundant carriers that can achieve photodynamic therapy (PDT) effects in human cervical cancer xenografts. PSs@BSAs enable specific tumor targeting and the precise accumulation of mitochondria driven by the positive charges of pyridocyanine. This will improve the biodistribution and pharmacokinetics in patients, minimize side effects, considerably reduce therapeutic threshold dosage, and ultimately increase the cancer phototherapeutic index. X-ray crystallography elucidates the two-stage assembly mechanism of PSs@BSAs. Femtosecond transient absorption (fs-TA) spectroscopy and quantum mechanical calculations reveal the implications of conformational dynamics at the excited state. Genome-wide ribonucleic acid (RNA) profiling of cervical carcinoma tissues treated with PSs@BSAs indicated that the photoablation of solid tumors was associated with the disruption of tumor angiogenesis, oxidative stress, and mitochondrial metabolism, including aerobic glycolysis and oxidative phosphorylation. The TASE strategy promotes an understanding of function-specific organelle-drug interactions, and it fully elucidates the interdisciplinary issues of chemistry, physics, and biological interfaces, thereby opening new horizons to inspire the engineering of organelle-targeted tumor-specific photosensitizers for biomedical applications.