Biomimetic Diselenide-Bridged Mesoporous Silica Nanoparticle As An Environmental Stimuli-Responsive Degradable Platform For Combined Cancer Therapy

As a severe threat to human health,cancer has become a public health problem affecting the sustainable development of society and economy.During the past few decades,nanomaterials have been widely used in the diagnosis and treatment of cancer.A characteristic example is mesoporous silica nanomaterial with controlled pore sizes depending on simple synthesis conditions,making it a promising clinical application.It is an effective strategy to improve degradation and drug release ability of mesoporous silicon nanomaterials by developing intelligent drug delivery systems which are sensitive to internal stimulus(e.g.,pH,redox potential,hypoxic and glucose)and external stimulus(e.g.,light,magnetic field,temperature,and ultrasound).The diselenide bond can be more easily cleaved either by oxidation to form seleninic acid or reduction to form selenol in different redox conditions.Thus,diselenide can be incorporated into structure-based intelligent drug delivery systems.Therefore,we take advantage of the diselenide bond’s unique chemical characteristics and synthesize the diselenide-bridged organosilica nanoparticles,which can degrade by the endogenous and exogenous stimuli(e.g.,oxidation,reduction,and X-ray).We construct a biomimetic nanoplatform exhibiting homologous targeting and immune-evading properties inherited from the source cancer cells by coating the tumor cell membrane.In this work,we achieved skeleton degradation in response to multiple environmental stimuli and controlled on-demand release of chemotherapeutics,overcoming the shortcomings of traditional mesoporous silicon.The details are as follows:1.Conventional mesoporous silica nanomaterials can cause accumulation toxicity in use due to poor degradability.Therefore,we aim to synthesize degradable mesoporous silicon materials.We used chemotherapeutic RNase A as a model drug to study the drug release of mesoporous silica nanomaterials under oxidizing conditions and reducing conditions.We found that disulfide-bridged mesoporous silica nanomaterials only achieved reduction responsive drug release,whereas diselenide-bridged mesoporous silica nanomaterials possessed oxidative/redox dual-responsive drug release behavior.After surface-cloaking with cancer-cell-membrane-derived fragments,MSNs@RNase A@CM showed homologous targeting and immune-invasion characteristics,resulting in improved in vitro and in vivo anti-cancer efficacy along with lower systemic toxicity.The presented work suggests a design for multi-responsive degradable nanocarriers for the controlled delivery of bio-macromolecules such as protein and nucleic acid therapeutics,with a possibility of on-demand release and low toxicity.2.We developed a new strategy for chemo-immunotherapy in which source cancer cell membrane coated,diselenide-bridged mesoporous organosilica nanoparticles serve as a biomimetic,X-ray/ROS-responsive drug carrier.Biodegradable diselenide-bridged mesoporous organosilica nanomaterial was designed for DOX loading and delivery and demonstrated degradation-controlled drug release by low-dose X-ray-induced cleavage of the diselenide bonds.Coating the mesoporous organosilica nanoparticles with cancer cell membrane-derived vesicles resulted in cancer cell targeting and immune system evasion.This chemo-immunotherapy boosts DOX-induced immunogenetic cell death and elicits systemic anti-tumor immunity,eradicating primary and metastatic tumors while minimizing off-target adverse effects.These biomimetic,radiation responsive diselenide-bond-bridged mesoporous organosilica nanoparticles have the potential to achieve efficient and safe chemo-immunotherapy outcomes in the clinic.The presented work suggests a design of radiation responsive carrier for the controlled delivery of therapeutic agents with a possibility of on-demand release and low systemic toxicity.3.We developed multifunctional diselenide-bridged mesoporous organosilica nanoparticles delivering immunogenetic cell death inducer to stimulate amplified antitumor immunity.KP1339-loaded immunogenetic cell death exhibited the Glutathioneresponsive drug release profile while induced intracellular glutathione depletion and reactive oxygen species production in 4T1 cells.The cancer cell membrane coating promoted the MON@KP1339-amplified immunogenetic cell death and boosted robust anti-tumor immunity,which demonstrated better tumor regression and metastasis inhibition in combination with an immune checkpoint inhibitor.The present work provided a biomimetic diselenide-bridged mesoporous organosilica nanomaterial with a possibility of coordination-responsive drug release and amplified immunogenetic cell death for efficient and safe cancer chemo-immunotherapy.In summary,we focused on diselenide-bridged mesoporous organosilica nanoparticles and designed diverse biomimetic drug delivery systems for highefficiency and low-toxicity cancer chemo-immunotherapy.Diselenide-bridged mesoporous organosilica nanoparticles exhibit great application potential because of their wide adaptability to realize multiple drug loading and release strategies.We performed a comprehensive physicochemical characterization,pharmacodynamic study,and safety evaluation of the diselenide-bridged mesoporous organosilica nanoparticles,which provides a theoretical and experimental basis for the application of degradable diselenide-bridged mesoporous organosilica nanoparticles.