Structural Design Of Manganese-based Nanoparticles For Antitumor Applications

As a global health problem,cancer has attracted wide attention and its treatment is still a hot topic in medical research.The current mainstream cancer treatment strategies have problems such as high mortality and high recurrence rate.However,with the continuous development of nanomedicine,many very promising nanomedicine drugs have been developed,some of which have been used in clinical treatment and successfully saved patients’lives.Nanomedicine uses the theory and method of nanobiotechnology to carry out medical research and practice on the basis of traditional medicine and modern medicine.Major breakthroughs and achievements in nano-drugs,nano-carriers and nano drug delivery have brought new opportunities for oncology medicine,nevel ideas and hopes for many problems that have not been solved at present,such as insoluble or insoluble drugs and low bioavailability.In the aspect of tumor diagnosis and treatment,photodynamic therapy（PDT）,chemodynamic therapy（CDT）,sonodynamic therapy（SDT）and other methods have made good progress.To treat a disease as complex as cancer,a single or independent treatment strategy may not be enough.Current drug delivery strategies increasingly favor a"multi-pronged"combination approach to achieve more effective treatment.Therefore,nano drug carriers that combine multiple functions and act through different mechanisms have become a new research trend.In addition,nanocallers respond to a variety of intrinsic biochemical factors in the tumor microenvironment（such as low p H,high H₂O₂/GSH levels,elevated redox potential,and overexpressed enzymes,etc.）as well as externally applied stimuli（such as light,ultrasound,or magnetic fields）to trigger site-specific drug release.Based on the abnormal physiological environment in tumor cells,a mangan-based hollow mesoporous nanocrystalline（H-Mn O₂）was constructed in this paper to deliver small molecule inhibitor Sulfasalazine（SSZ）and block endogenous synthesis of GSH.At the same time,the modification of HMME on the surface of nanocapsules produced ROS under the stimulation of ultrasound（US）,and the synergistic effect resulted in a sharp increase in the intracellular ROS level.In the process of ROS accumulation and GSH consumption,the intracellular redox homeostasis is seriously damaged.The multipathway action of the nano-preparation can further induce iron death/apoptosis of tumor cells.In addition,tumor-specific degradation of Mn O₂ nanocoliters helps relieve hypoxia in tumor areas and leads to apoptosis through enhanced sonodynamic therapy and chemodynamic therapy.On the other hand,regional oxygenation significantly downregulates the expression of activating transcription factor 4（ATF4）,which can synergize with the release of sulfasalazine to inhibit the downstream cystine antiporter x CT.Biosynthesis of GSH is sufficiently interrupted by the x CT suppression,leading to the reduction of glutathione peroxidase 4（GPx4）level.The resultant excessive lipid peroxides promote intense ferroptosis to motivate cell death.On this basis,splendid treatment outcome by H-Mn O₂@HMME/SSZ（MHS NPs）is substantiated both in vitro and in vivo,thanks to the elicitation of antitumor immunity.Taken together,this paradigm provides an insightful strategy to evoke drastic ferroptosis/apoptosis toward therapeutics and may also expand the eligibility of manganese-derived nanoagents for medical applications.