Tumoral Endogenous Clues Homeostasis Modualating Based-Nanodrug Platform For Tumor Therapy

Globally,cancer remains one of the greatest threats to human health and one of the diseases with the highest case fatality rate.At present day,the most commonly used methods of clinical cancer treatment are chemotherapy,hormone therapy,immunotherapy,photodynamic therapy,radiotherapy,stem cell transplantation,surgical resection and so on.However,these treatments often have serious problems,such as high risk,low specificity,poor biodistribution,low treatment efficiency and related complications.The emergence of nanomedicine therapy has brought about a paradigm shift from traditional therapy to precision medicine.Nanoparticles can deliver usually insoluble drugs to local and distant tumor sites in a better way,reducing the systemic side effects usually associated with conventional drug therapy.Due to the heterogeneity of tumors and the complexity of the tumor microenvironment（TME）,the development of effective anticancer therapies remains a daunting and difficult challenge despite substantial human,material,and financial resources.As a result,therapeutic strategies based on the regulation of TME have attracted more and more attention.In particular,the abnormal expression of biomarkers in the TME,such as hydrogen peroxide（H₂O₂）,glutathione（GSH）,reactive oxygen species（ROS）,Glucose,oxygen（O₂）,acidity（p H）and inflammation-related factors,caused changes in the metabolism of tumor cells and lead to heterogeneous proliferation of tumors.Therefore,there is an urgent need to develop a nano-drug that can respond to the stimulation of TME,and achieve high targeting to tumor sites while reducing the toxic and side effects on normal tissues.In this paper,two multifunctional nanomedicine platforms are proposed to reshape the TME.Firstly,a multi-enzyme platform（PGMA）based on urchin-like platinum（Pt NUs）nanoparticles was constructed,in which glucose oxidase（GOx）was coupled to Pt NUs,and then MnCO and 3-AT were loaded by hydrophobic interaction and electrostatic interaction.TME stimulation with slightly acidic and high levels of H₂O₂ can promote MnCO degradation and then induce the release of CO gas,3-AT,and Mn^2+/3+.Exposure of GOx triggers intratumoral glucose depletion and accelerates the catalytic efficiency via O₂ decomposed by Pt-catalyzed H₂O₂.Meanwhile,Mn^2+/3+-mediated Fenton-like reaction induced the increase of intracellular reactive oxygen species（ROS）.Thus,CO-released gas therapy,glucose depletion-induced tumor starvation therapy,and ROS-triggered chemodynamic therapy achieve synergistic disruptive effects on mitochondrial function.Importantly,the released 3-AT can inhibit the activity of endogenous catalase,effectively increasing the intracellular H₂O₂ level to compensate for its consumption and providing incremental reactants for the cascade reaction.Finally,the therapeutic results both in vivo and in vitro demonstrate the superior antitumor ability of PGMA.Subsequently,in order to further explore the ion balance system of TME,we established a multifunctional nanoplatform of p H-responsive amorphous CaCO₃（CTC）.Specifically,we loaded carvacrol（TRPM7 channel inhibitor）inside CaCO₃ by one-pot method and modified the surface with TPP（sonosensitizer）to achieve ion balance therapy（IBT）and ultrasound-activated sonodynamic therapy（SDT）for tumors.The weak acidic TME can promote the decomposition of CaCO₃,and the release of Ca²⁺can induce the rapid formation of calcified nodules,which is enhanced by carvacrol inhibiting the antagonistic effect of Mg²⁺on Ca²⁺.In addition,TPP-mediated SDT can produce high levels of ROS,which not only interrupt mitochondrial respiration to trigger apoptosis,but also exacerbate the disturbance of intracellular redox homeostasis.Importantly,this dysregulation of intracellular redox homeostasis can effectively activate antitumor immunity through immune checkpoint blockade and trigger immunogenic cell death（ICD）.Overall,this paradigm emphasizes that the therapeutic regimens that interfere with intracellular redox homeostasis through Ca²⁺/Mg²⁺regulation significantly inhibit tumor growth under the synergistic effect of SDT and ICD,and show excellent systemic toxicity,which may promote more medical applications of nano-drugs based on endogenous cues balance regulation in critical diseases.