Biodegradability Regulation And Performance Research Of Mesoporous Silica-based Nanocarriers

The fast development of nanobiotechnology has catalyzed the fabrication of various nanosystems with diverse nanostructures and compositions for biomedicine.Based on the high surface area,high pore volume,tunable pore size and nanostructure,abundant surface chemical property,good thermostability and high biocompatibility,mesoporous silica nanoparticles?MSNs?have been extensively explored for drug delivery,bio-imaging,biosensing and synergistic cancer therapy.However,the intrinsic inert nature of-Si-O-Si-framework makes it difficult to biodegrade in mild physiological conditions.The reluctant biodegradation of MSNs may lead to the accumulation of the nanoparticles within the body,leading to a potential bio-toxicity.Therefore,the biodegradability issue of MSNs is one of the most critical roadblocks in the further clinical translation.To solve this problem,three kinds of methods have been developed to improve the biodegradability of MSNs,i.e.,sodium-thermic reduction,organic-inorganic hybridization and metal ion-doping.The topological transformation of MSNs endows them with specific functions simultaneously and enables silica-based nanosystems multifunctionalization.The systematic research has been carried out and summarized as follows:1.Method of sodium-thermal reduction improving the biodegradability of MSNs-based nanocarriersd.Herein a new strategy is proposed to change the inert framework of MSNs,which snatched part of oxygen atoms within the framework of silica nanoparticles via“sodium-thermal reduction”.The obtained nanoparticles with a few silicon nanodots?named Si-MSNs?show a higher ratio of oxygen atoms to silicon atoms than traditional MSNs and more structural defects,which made it as a kind of biodegradable nanocarriers.Moreover,the mesoporous nanostructure of traditional MSNs is still maintained after the reduction reaction,which endows it with good capacity of drug loading and delivery.2.Biodegradability regulation of MSNs-based nanocarriers via organic-inorganic hybridization?1?Mesoporous organosilica nanoparticles:Morphology modulations and redox-responsive biodegradability for tumor-specific drug delivery.Monodispersed and molecularly organic-inorganic hybrid mesoporous organosilica nanoparticles?MONs?with framework incorporated physiologically active thioether bonds have been fabricated with controllable nanostructure,composition and morphology on the largescale,which provides the material foundation for exploring the versatile biomedical applications of organosilica nanosystems.Becaues of the successful insertion of disulfide linkages in the framework of MONs,the obtained hybrid MONs of less than 50 nm in diameter exhibit the unique reduction-responsive biodegradation behavior,and the biodegradation rate is significantly higher than that of traditional MSNs with pure inorganic-Si-O-Si-framework.The reductive microenvironment-triggered biodegradation of MONs induces the concurrent reduction-responsive chemotherapeutic drug releasing from MONs in tumor tissue,enabling tumor-specific drug delivery.Importantly,these biocompatible and biodegradable MONs exhibit enhanced tumor-suppressing effect for combating cancer.Based on the facile and large-scale fabrication of MONs with controllable key nanostructure/composition/morphology parameters,unique tumor microenvironment-responsive biodegradation behavior and high performance for drug delivery,the MONs therefore are considered as one of promising nanocarriers for potential clinical translation.?2?Hematin loaded biodegradable organosilica nanosystem for high-efficient tumor therapy and mechanism study of the induced ferroptosis.Without needs of anti-cancer drugs and based on Hollow Mesoporous Organosilica Nanoparticles?HMONs?,the hematin loaded biodegradable organosilica nanosystem,modified with glucose oxidase?GOx??named as GOx-hematin@PEG/HMONs?,has been designed to induce tumor cells ferroptosis.The ingredients of nanosystem are all biosafe and nontoxic.The mechanism of ferroptosis induced by GOx-hematin@PEG/HMONs is based on the increase of Fe-dependent reactive oxide species?ROS?,which is induced by two steps of catalysis process:1)GOx catalyze the glucose oxidation to generate H₂O₂;2)Hematin catalyze the Fenton reaction of H₂O₂ to generate hydroxyl radicals?one kind of ROS?.Besides,these kinds of nanosystems without anticancer drugs do exhibit enhanced tumor-suppressing effect for combating cancer,which has been verified on tumor-bearing mice.3.“Metal ion-doping”method improving the biodegradability of MSNs-based nanocarriers.?1?“Manganese extraction”strategy enables tumor-sensitive biodegradability and theranostics of nanoparticles.A novel“metal ion-doping”approach has been developed to endow inorganic mesoporous silica-based nanoparticles with tumor-sensitive biodegradation and theranostic functions,simply by topological transformation of mesoporous silica to metal-doped composite nanoformulations.“Manganese extraction”sensitive to tumor microenvironment was enabled in manganese-doped hollow mesoporous silica nanoparticles?designated as Mn-HMSNs?to fast promote the disintegration and biodegradation of Mn-HMSNs,further accelerating the breakage of Si-O-Si bonds within the framework.The fast biodegradation of Mn-HMSNs sensitive to mild acidic and reducing microenvironment of tumor resulted in much accelerated anticancer drug releasing and enhanced T₁-weighted magnetic resonance imaging of tumor.A high tumor-inhibition effect was simultaneously achieved by anticancer drug delivery mediated by PEGylated Mn-HMSNs,and the high biocompatibility of composite nanosystems was systematically demonstrated in vivo.This nanoplarform provides a feasible approach to realize the on-demand biodegradation of inorganic nanomaterials simply by“metal ion-doping”strategy,paving the way to solve the critical low-biodegradation issue of inorganic drug carriers.?2?Magnesium-engineered silica framework for Mg²⁺-triggered chemotherapy.To solve the dissatisfactory biodegradability and pre-drug leakage with non-specificity to lesion sites of MSNs,herein a framework-engineering strategy is introduced to simultaneously achieve enhanced biodegradability and controllable drug releasing,based on the mostly explored MSNs-based nanosystems.The framework of mesoporous silica has been engineered by the direct Mg doping via a generic dissolution and regrowth approach,and it could transform into the easy biodegradation of magnesium silicate nanocarriers.Especially,such magnesium silicate nanocarriers can respond to the mild acidic environment of tumor tissue,causing the fast breaking up and biodegradation of the silica framework.More interesting,the released Mg²⁺could further activate Mg²⁺-dependent DNAzyme on the surface of Hollow Mesoporous Magnesium Silicate Nanoparticles?HMMSNs?to cleavage the RNA-based gatekeeper,which further accelerated the releasing of loaded anticancer drugs.Therefore,the enhanced anticancer efficiency of chemotherapeutic drugs assisted by the biodegradable intelligent HMMSNs has been achieved.The high biocompatibility of nanocarriers and biodegradation products have been demonstrated and could be easy excreted via feces and urine for guaranteeing their further clinical translation.