2D Ultrathin Mxene-based Drug Delivery Nanoplatform For Synergistic Photothermal Ablation And Chemotherapy Of Cancer

Sincere the first discovery of graphene in 2004,^[1]two-dimensional（2D）materials have attracted tremendous attention in scientific community because of their unique ultrathin planar nanostructure,abundant compositions and corresponding physiochemical properties,showing broad applications in diverse fields.^[2,3]In addition to aforementioned 2D graphene,a large number of family members of 2D functional materials have been discovered and developed,including metals,metal oxides,transition-metal dichalcogenides（TMDCs）,black phosphorus,clay materials（e.g.,layered double hydroxides and laponite）,etc.^[4-9]Especially,the fast progress of material-synthetic chemistry has achieved the direct exfoliation of 2D ultrathin ceramic nanosheets directly from layer-structured solid and hard MAX-phase ceramics,which is termed as MXene by Gogosti,Barsoum and colleagues.^[10-12]MXenes are typically produced by extraction of A-element from MAX-phase ceramics,where M means a transition metal,A means an A group element,and X is C or N such as Ti₃AlC₂.^[12-16]Because of the abundant family members of MXenes and their excellent electronic conductivity,they have been developed for versatile applications,which however,are mainly focused on the energy storage and conversion fields.^[17-19]The exploring of these new emerging MXenes for other applications is therefore expected to significantly broaden their unique physiochemical properties to satisfy different requirements of diverse applications and further enhance the industrial-translation potentials.This work targets the biomedical applications of MXenes,especially on combating the cancer.The ultrathin planar nanostructure of 2D bio-nanosystem endow them with large surface area,which provides the abundant anchoring sites for therapeutic drug molecules just like graphene,MnO₂,black phosphorus or TMDCs nanosheets.^[20-25]Therefore,they can be developed as the drug-delivery nanosystems for efficient intracellular drug delivery.Especially,we and other researchers recently have demonstrated that 2D titanium carbide（Ti₃C₂）MXene nanosheets are intrinsically featured with photothermal-conversion capability,which can be further developed as the photothermal nanoagents for cancer hyperthermia upon the external irradiation by near infrared（NIR）laser,showing their potential applications in biomedicine.^[26-30]It is further expected that the rational combination of structural feature（2D planar structure for drug delivery）and physiochemical property（photothermal conversion for hyperthermia）of Ti₃C₂ MXene could achieve the synergistic chemotherapy and photothermal ablation of cancer,thus causing the high therapeutic outcome on combating cancer.Herein,we report,for the first time,on the exploring of the delivery performance of 2D Ti₃C₂ nanosheets for chemotherapeutic drugs,and their further combination of photothermal conversion for synergistic photothermal therapy（PTT）and chemotherapy,which has been systematically evaluated and demonstrated both in vitro and in vivo.It has been demonstrated that Ti₃C₂ MXene could act as the desirable drug-delivery nanosystem with high drug-loading capacity and stimuli-responsive drug-releasing performance upon inner or external triggering.By the integration of PTT-based therapeutic modality with chemotherapy,the as-developed 2D Ti₃C₂ nanosheets has achieved the synergistic and complete eradication of tumor in vivo.This work represents the progress of exploring the drug-delivery applications of 2D MXenes and their synergistic therapeutic performance on efficient cancer therapy.Originality and Novelties.（1）Efficient drug loading and controlled drug releasing based on 2D Ti₃C₂ MXene.Ti₃C₂ MXenes,as a novel drug-delivery nanosystem,not only possess the high drug-loading capability of as high as 211.8%,but also exhibit both pH-responsive and near infrared（NIR）laser-triggered on-demand drug-releasing performance.（2）Synergistic photothermal hyperthermia and chemotherapy for complete eradication of cancer.Based on the high photothermal-conversion capability of 2D Ti₃C₂ MXenes,they have been further explored for highly efficient tumor eradication without reoccurrence by synergistic Ti₃C₂-assisted photothermal ablation and chemotherapy,which has been systematically demonstrated both in vitro and in vivo.These 2D Ti₃C₂MXenes have also been demonstrated as the desirable contrast agents for photoacoustic imaging,showing the potential for diagnostic-imaging guidance and monitoring during synergistic therapy process.（3）High biocompatibility and easy excretion of Ti₃C₂ MXenes.The high in vivo histocompatibility of Ti₃C₂ and their easy excretion out of the body have been evaluated and demonstrated,showing the potential high biosafety for further clinical translation.