Ultrasound-responsive Nanomaterials With Cancer Cell Membrane Camouflage For Homotypic Tumor Therapy

Sonodynamic therapy（SDT）is a novel non-invasive cancer treatment,which uses ultrasound（US）to stimulate sonosensitizers enriched in tumor sites,resulting in the production of reactive oxygen species（ROS）.ROS can cause damage to cancer cells through intense oxidation of cellular lipids,proteins and DNA components,leading to precise tumor elimination.Due to high tissue-penetration and biosafety of ultrasound,SDT is highly promising for the treatment of deep-seated tumors.Sonosensitizers are the key to achieve efficient SDT.Since most conventional organic sonosensitizers are hydrophobic,they are easily aggregates in the blood,which greatly reduces their sonosensitization and blood circulation time.Moreover,the lack of targeting ability of most sonosensitizers causes unsatisfactory enrichment of sonosensitizers in tumors after intravenous injection,which leads to limitations of the anti-cancer effect of sonosensitizers.In order to prolong the blood circulation time of conventional organic sonosensitizers and enhance their tumor-targeting ability,this study constructed two sonosensitizers-loading nanoplatform that could target tumors by using hemoporfin as the sonosensitizers and poly（lactic acid）and Cu₉S₈ as carriers,supplemented with cancer cell membrane camouflage.Both nanomaterials exhibited biosafety,sonodynamic effect,long-term blood circulation time,and tumor targeting ability,which achieved efficient tumor treatments.The main results are as follows.（1）Synthesis of cancer cell membrane-camouflaged hemoporfin@poly（lactic acid）for targeted SDT of homotypic tumorsTo enhance the blood circulation time and tumor-targeting ability of hemoporfin,hemoporfin was loaded into poly（lactic acid）by reverse micellar-solvent evaporation method（H@PLA）,and then CT26 cell membrane was camouflaged on the surface of H@PLA by physical extrusion（H@PLA@CCM）.The hemoporfin loaded in H@PLA@CCM can generate singlet oxygen（¹O₂）with sonodynamic effect under the stimulation of ultrasound.Due to the camouflage of CT26 CCM,H@PLA@CCM showed higher cellular uptake efficacy by mouse colon cancer（CT26）cells than H@PLA,and were more readily phagocytosed by CT26 cells compared to mouse breast cancer cells（4T1）.After the intravenous injection,the blood circulation half-life time of H@PLA@CCM is 3.23h which is 4.3-time that of H@PLA.In addition,H@PLA@CCM with high biosafety,homotypic targeting ability and sonodynamic effect induced significant apoptosis and necrosis of tumor cells,achieving a powerful tumor suppression effect.（2）Synthesis of cancer cell membrane-modified hemoporfin-Cu₉S₈ for targeted PTT/SDT of homotypic tumorsTo enhance the blood circulation time and tumor-targeting ability of hemoporfin as well as to enhance therapy effects,CT26 cancer cell membrane-camouflaged hollow Cu₉S₈ loaded with hemoporfin（H@Cu₉S₈@CCM）was designed as a multifunctional therapeutic platform for targeted PTT-SDT of homotypic tumors.H@Cu₉S₈@CCM possesses high photothermal conversion efficiency（39.8%）and ¹O₂ yield.H@Cu₉S₈@CCM have a longer blood half-life（3.17 h）which is6.47 times than that of H@Cu₉S₈.And tumor accumulation content（18.75 ID/g）of H@Cu₉S₈@CCM nanomaterials is 1.94 times than that of H@Cu₉S₈ nanomaterials.After intravenous injection,the H@Cu₉S₈@CCM completely eliminated tumors under the stimulation of NIR laser and ultrasound due to the high enrichment efficiency in tumors and the synergistic effect of PTT-SDT.Therefore,H@Cu₉S₈@CCM can be used as a multifunctional therapeutic platform with great potential in the PTT-SDT of homotypic tumor.