Near-Infrared Responsive Dual-Transformable Nanoassemblies For Combined Cancer Therapy

Cancer has become one of the major diseases threatening human physical and mental health and causing huge economic burden in China and even in the world today.The diagnosis,treatment of malignant tumors as well as the suppression of their recurrence remain an urgent problem.Nanotechnology has unique advantages in improving the bioavailability of poorly soluble substances,achieving controllable and targeted drug release,and integrating different therapeutic modalities in the same platform.However,it faces various biological barriers for practical applications,including blood circulation,trans vascular transport,malformed tumor vessels,and dense tumor extracellular matrix,resulting in most of nanoparticles are mainly localized around the peripheral of the tumor,and it is difficult to penetrate into the tumor to exert cell killing effect.In order to improve tumor accumulation and penetration of nanoparticles for safe and effective combined cancer therapy.Here,a near-infrared(NIR)light-driven nanosystem with size and charge dual-transformation is developed,and its physicochemical properties,efficacy and safety are investigated.The core-shell nanoassembly is realized by integrating diselenide-bridged mesoporous organosilica nanoparticles(MONs)as a reactive oxygen species(ROS)-responsive core loaded with doxorubicin(DOX),and an indocyanine green(ICG)-hybrid N-isopropyl acrylamide layer as a thermosensitive shell.The nanoassemblies are uniform and stable,especially,negatively charged thermosensitive layer prevents DOX leakage,rendering prolonged blood circulation time.Upon 808 nm NIR light irradiation(0.25 W/cm2),mild photothermal effects(43.2℃)facilitate the dissociation of the thermosensitive shell to achieve negative-to-positive surface charge reversal(-12.03 mV to+13.5 mV).Meanwhile,ICG-generated ROS cleave the diselenide bond of the organosilica core,resulting in rapid matrix degradation that produces DOXcontaining smaller fragments(115 nm to 20 nm),and then substances such as hydrogen peroxide(H2O2)in tumors promote the further degradation of smaller particles and rapid drug release.Due to the charge-size conversion induced by NIR and H2O2,the release amount of DOX in ID@M-N reaches 80%within 72 h,which is 16 times that of the group without light and oxidizing substances in vitro.Such a light-responsive nanoassemblies can carry drugs deep into the tumor and spread throughout the whole tissue in vivo,whereas drugs in the non-light group could not be efficiently transport across blood vessels into the tumor.Finally,the ID@M-N implement sufficient light responsive chemotherapy,along with evoking robust immunogenic cell death effects at tumor site and promoting tumor recognition and elimination by the immune system.With the combination of a programmed cell death protein-1(PD-1)checkpoint blockade,the nanosystem not only remarkably blocks primary tumor growth with the tumor inhibition rate up to 94.5%,but also inhibits the pulmonary metastasis of breast cancer with greatly alleviating the toxic and side effects of free drugs.In conclusion,this study develops a light-responsive charge and size dualtransformable system via nanotechnology to improve the deep distribution of drugs at tumor site,and integrates organically NIR phototherapy,chemotherapy and immunotherapy using nanomedicine fabricated by a degradable drug loaded core with a thermosensitive shell for efficient and safe comprehensive treatment of breast cancer.