Albumin Modulated Homodimer as an Efficient Photosensitizer for Long‐Term Imaging‐Guided Tumor Therapy Directed with Sunlight Irradiation

The reactive oxygen species (ROS) amplification caused by inevitable plasma albumin encapsulation is still a challenge to circumvent the systemic adverse effects in the photodynamic therapy (PDT) process. Herein, a disulfide bond linked homodimer, Cy1280, which is modulated by albumin to accurately balance the fluorescence and ROS generation and exhibit a weak fluorescence and sealed PDT effect during blood circulation, is exploited. Cy1280 can be specifically internalized and dispersed at the tumor site via Organic Anion Transporter Proteins (OATPs) and thiol-disulfide exchange mediated synergistic uptake and activated after mild sunlight irradiation (100 ± 5 Klx) to sensitize neighboring oxygen in cellular mitochondria to execute direct protein dysfunction effect. The dynamic covalent chemistry (DCC) facilitates prolonged and sustained retention in tumors (>336 h) and demonstrates the efficacy of imaging-guided solid-tumor therapy in tumor-bearing BALB/C mice. This study resolves the inevitable stubborn impotent tumor penetration caused by bulky-sized nanoparticles and high interstitial pressure of tumor with synergistic uptake manner, the long-term circulation and sealed PDT manipulated with albumin also improve the whole body phototoxic symptom. The advantageous feature of Cy1280 provides a promising candidate for overcoming the off-target phototoxicity and inadequate accumulation challenges in clinical translation with photosensitizers (PSs).