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

Abstract 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).