Host–Guest Polypyrrole Nanocomplex for Three‐Stimuli‐Responsive Drug Delivery and Imaging‐Guided Chemo‐Photothermal Synergetic Therapy of Refractory Thyroid Cancer

: Despite the good prognosis of the low-risk thyroid cancer, there are no truly effective treatments for radioactive iodine-refractory thyroid cancer. Herein, a novel theranostic nanoplatform, as well as a smart doxorubucin (DOX) delivery system is fabricated. Gelatin-stabilized polypyrrole nanoparticles are reported for the first time. The combination of gelatin-stabilized polypyrrole and cyclodextrin-DOX complexes enabling three-stimuli-controlled drug delivery, including the enzyme-sensitive, pH-sensitive and photothermal-sensitive drug release, exhibiting a new way to equip photothermal agents with precisely controlled drug delivery. Anti-galectin-3 antibodies are utilized as the targeting molecules of nanoparticles in the first time, which surprisingly increase intracellular DOX uptake by enhanced clathrin-mediated endocytosis, showing galectin-3 can be employed as a highly efficient target of drug delivery systems. The nanoparticles achieve excellent photoacoustic imaging effect, enabled chemo-photothermal combined therapy with pinpointed drug delivery. Compared to free DOX, these multifunctional nanoparticles decrease the heart damage, but greatly increase the tumor/heart ratio of DOX concentration by 12.9-fold. The tumors are completely eradicated without any recurrence after the in vivo combined therapy. To the best of the authors' knowledge, this is also the first report to apply photoacoustic imaging-guided chemo-photothermal therapy for thyroid cancer, showing great potential to solve the dilemma in thyroid cancer therapy.