Calcium Homeostasis Regulating Materials Alter Cell Fate For Treatment Of Diseases

The close correlation between diseases and cell fate lead researchers to fouced on the therapeutic strategies by altering cell fate.However,the diversity of parameters that could influence cell fate make it difficult to directionally alter cell fate by adjusting single parameter in vivo,and more importantly,systematize the treatment methods for different diseases.Actualy,cell fate alteration’s essence is the conversion of external output stimuli into internal input signals by signal transmission systems to change the cell life activities,which determine the life and death of cells.Calcium ions(Ca²⁺)is the secondary messenger in cells,and calcium homeostasis represents their intracellular concentration and distribution dynamic balance,which could alter cell fate to different directions.Calcium homeostasis is closely related to Ca²⁺channels,Ca²⁺-ATP pumps,Na⁺/Ca²⁺exchangers and calcium binding proteins（CBP）,and it has unique features of spatio-temporal universality,regional differences,dynamic reversibility and signal diversity.Based on this,a series of calcium-homeostasis-regulating nanomaterials were designed and synthesized to change cells fate in this work,and their feasibility and universality were systematically studied for treatment of diseases.The researchs mainly includes the following three aspects:1.Calcium homeostasis imbalance reverser protecting bone marrow mesenchymal stem cells（MSCs）for ischemic stroke treatment.The MSCs therapy is one of the most effective therapeutic strategies of ischemic stroke.However,excess reactive oxygen species（ROS）and Ca²⁺in ischemia and hypoxia pathological environment extremly reduce the MSCs’survival efficiency and differentiation specificity,leading to inefficient MSCs therapy.Meanwhile,the existing MSCs-protecting methods are limited by the problems of low efficacy and single function,resulting in ineffective protection of MSCs and low treatment efficiency.Here,based on the cell-fate-controlling ability and dynamic reversibility of calcium homeostasis,the calcium homeostasis imbalance reverser（NPANs）was designed and prepared to scavenge ROS and buffer Ca²⁺in MSCs.The Ca²⁺chelating sites formed by polydopamine（PDA）and alendronate（ALD）could reverse calcium homeostasis imbalance in MSCs,protecting MSCs for ischemic stroke treatment.The components in this strategy have two main functions:（1）Phenolic hydroxyl（-OH）in PDA scavenged ROS and eliminated the oxidative stress in MSCs in the pathological environment.（2）ALD chelated excess intracellular Ca²⁺in MSCs,reversing the calcium homeostasis imbalance,changing the cells fate from apoptosis to survival for efficient MSCs protection.Both in vitro and in vivo experimental results showed that NPANs could reverse the pathological calcium homeostasis in MSCs and increase the survival rate of MSCs,significantly improving the brain blood flow in the middle cerebral artery occlusion（MCAO）model in vivo.This research breakthrough the limitations of exsisting MSCs therapy strategies,which could be referred for more ischemic stroke treatment methods.2:Calcium homeostasis imbalance initiator triggering tumor cells apoptosis for tumor therapy.Calcium homeostasis imbalance can induce apoptosis of both MSCs and tumor cells,which has been acknowledged and utilized in cancer treatment.The developed tumor therapy strategies based on calcium imbalance mainly focused on exogenous Ca²⁺introduction,but the risks such as cardio cerebrovascular disease induction seriously limited their further application in clinical research.Based on this,a calcium homeostasis imbalance initiator（UC-ZIF/BER）activated by near infrared light（NIR）controlled-release nitric oxide（NO）was designed and prepared to regulate calcium imbalance in cancer cells.Upconversion luminescent nanoparticles（UCNP）and ZIF-82 were used as the core shell,respectively,with calcium ATP pump inhibitor-berbamine（BER）loaded in the pore.Under the dual activation of NIR and tumorous low p H,UC-ZIF/BER released NO to turn on ryanodine receptor（Ry R）calcium channel in endoplasmic reticulum（ER）,inducing endogenous calcium overload and altering tumorous cells fate from proliferation to apoptosis for efficient tumor killing.In this strategy,the UC-ZIF/BER released NO and BER in response to NIR,and functioned from two aspects:（1）NO diffused into tumor cells and effectively opened Ry R channels in tumorous cells ER,transporting ER Ca²⁺into cytoplasm and elevating instantaneous Ca²⁺level in tumor cells;（2）BER turned off Ca²⁺ATP pump to inhibit Ca²⁺efflux,enhancing Ca²⁺overload induced apoptosis for tumor killing.Both in vitro and in vivo experiments showed that UC-ZIF/BER could significantly increase the Ca²⁺concentration and destroy mitochondrial respiratory chain to induce oxidative stress,which transformed tumor cell fate from proliferation to apoptosis for tumor therapy.This study achieved efficient and safe tumor treatment by utilizing the function of calcium homeostasis to induce cancer cells apoptosis,which provided referential ideas for cancer treatment.3:Calcium homeostasis remodeler blocking cancer-nerve signal transmission for bone cancer pain treatment.Currently,treatment methods of bone cancer pain are limitated by the lack of dual functions of tumor depression and pain inhibition.Meanwhile,analgesics have disadvantages of low-efficiency,short-acting,side-effects,and addiction effects.Actually,the refractoriness to bone cancer pain arises from aberrant calcium homeostasis due to the interaction of bone tumors with sensory nerves,and dissecting the signaling communication between bone tumors and nerves would be effective in treating bone tumors and suppressing neuropathic bone cancer pain.This study designed and prepared a calcium homeostasis remodeling regulator（LAD）with tumor nerve signal blocking function.LAD was composed of magnesium aluminum layered double hydroxide（LDH）,with Trk A receptor antagonist-AZ-23loaded in intralayer and ALD targeting ligand in outer surface.LAD could be targeted by ALD to the bone tumor tissue,simultaneously inhibiting the hyperalgesia and tumor proliferation by responding to the excessive H⁺in the bone tumor area and decomposing to release AZ-23 and Mg²⁺.The therapeutic function of LAD to bone cancer pain are mainly from the following three aspects:（1）LDH inhibited the activation of TRPV1 calcium channel by directly neutralizing the excess H⁺in the tumor area and changed sensory nerve from neuronal excitability to resting state,inhibiting pain signal generation and blocking the nerve-to-cancer calcium crosstalk effect,which could simultaneously achieve pain relief and tumor inhibition;（2）AZ-23,an antagonist of the NGF/Trk A pathway released by LAD,could effectively block the growth promoting effect of nerve growth factor（NGF）secreted by tumors,inhibiting the pain sensitization and tumor proliferation of sensory nerve fiber hyperplasia;（3）Mg²⁺elevated osteoblastic activity of bone tissue in the bone tumor area to repair bone tumor induced bone tissue breakage and decreased osteoclastic activity.The three components synergistically inhibited bone tumor proliferation,bone cancer pain as well as bone histolysis with high efficiency for treatment of bone cancer pain.In vitro and in vivo experimental results showed that the pain threshold of bone tumor model mice was elevated by nearly 30%within 21 days observation period,and the tumor growth inhibition rate was as high as 50%within 28 days observation period,indicating that LAD not only significantly attenuated bone tumor induced bone cancer pain with bone cancer pain inhibition function,but also greatly reduced the volume of bone tumor and possessed the therapeutic effect on bone tumor.This study took the aberrant calcium homeostasis in tumor nerve interaction as a unique entry point to design and synthesize nanofunctional materials to remodel the cancer-nerve calcium homeostasis,which broke through the incurable bottleneck of conventional therapeutic means for bone cancer pain,hopefully providing borrowing research ideas for designing tumor treatment and cancer pain inhibition strategies from the perspective of cancer neuroscience.