Constructing Stimuli-Responsive Nanosystems For Disease Treatment

Stimuli-responsive nanosystems that are sensitive to internal signals(pH,GSH,H2O2,ATP,enzyme,and glucose)or external stimuli(ultrasound,light,electric fields,and magnetic field),and interact with or are actuated by them for a range of biomedical applications.Recently,numerous stimuli-responsive nanosystems have been developed for the diagnosis and treatment of many diseases,including thrombus,bacterial infections,cancer,inflammatory bowel disease,diabetes,and so on.Compared with traditional nanomedicines,stimuli-responsive nanosystems with higher controllability,safety,and better efficacy can achieve site specific activation to exert therapeutic effects,which greatly reduced the toxic and side effects,and achieved more precision therapy.Here,to overcome current problems of the stimuli-response system(limited therapeutic effects in complex biological systems,recurrent disease,etc),we designed and constructed a series of novel and functional stimuli-response systems and applied them for the treatment of diseases.The main results are summarized as follows:1.Recently,antimicrobial photodynamic therapy(aPDT)has been considered as an attractive treatment option for biofilms ablation.However,even very efficient photosensitizers(PSs)still need high light doses and PS concentrations to eliminate biofilms due to the limited penetration and diffusion of PSs in biofilms.Moreover,the hypoxic microenvironment and rapid depletion of oxygen during PDT severely limit their therapeutic effects.Herein,for the first time,a porphyrin MOF(pMOF)dots-based nanoplatform with effective biofilm penetration,self-oxygen generation and enhanced photodynamic efficiency was synthesized for bacterial biofilms eradication.The function-adaptive nanoplatform was composed of pMOF dots encapsulated by human serum albumin(HSA)-coated manganese dioxide(MnO2).The pH-/H2O2 responsive decomposition of MnO2 in biofilms triggered the release of ultrasmall and positive-charged pMOF dots and simultaneously generated O2 in situ to alleviate hypoxia for biofilms.The released pMOF dots with high ROS yield could effectively penetrate into biofilms,strongly bind with bacterial cell surface and ablation bacterial biofilms.Importantly,such a nanoplatform could realize great therapeutic outcomes for the treatment of Staphylococcus.aureus infected subcutaneous abscess in vivo without damage to healthy tissues,which offers a promising strategy for efficient biofilms eradication.2.Traditional thrombolytic drugs offer limited outcomes due to short circulation half-life and low utilization.Herein,we have designed and constructed a biological mediator-propelled nanosweeper for highly efficient nonpharmaceutical thrombolysis and prevention of thrombus recurrence.Under the near-infrared(NIR)light irradiation,the nanosweepers were activated to trigger nitric oxide(NO)release,which propelled the nanosweepers to penetrate deeply into the thrombus and resulted in enhanced site-specific mechanical and photothermal thrombolysis.The experimental evidence confirmed that the ingenious nanosweeper displayed excellent site-specific thrombolytic efficacy even compared with the clinical thrombolytic drug.Meantime,as a biological mediator,the release of NO could effectively prevent thrombus recurrence in vivo.Overall,we anticipated that nanosweeper would provide a promising strategy for the treatment of thrombus.3.Many surface-charged materials are exhibited to disturb the electron transfer of bacteria for antibacterial treatment.However,the finite surface charge or uncontrolled electron transfer of these nanoplatforms limited their further clinical applications.Herein,a magnetoelectrically ignited nanozyme-eel was developed,which could generate the abundant surface charges upon ignition of the alternating magnetic field,leading to the controllable electron transport burst between the nanozyme-eel and bacteria for highly efficacious treatment of implant-associated bacterial infections.More importantly,this magnetoelectrically ignited nanozyme-eel possessed outstanding biocompatibility and biosafety for future clinical applications.This work may open up a new way for the treatment of implant-related bacterial infections and promote the research and applications of magnetoelectricity-based materials in other fields.4.Conventional strategies for inflammatory bowel diseases can merely relieve inflammation and excessive immune response,and fail to solve the underlying causes of IBD,such as the disrupted gut microbiota and intestinal barrier.Recently,natural probiotic has shown tremendous potential for the treatment of IBD.However,the probiotic is not recommended for IBD patients as it may cause bacteremia or sepsis.Herein,for the first time,we constructed the artificial probiotics(Aprobiotics)with the yeast shell as the membrane of Aprobiotics and artificial enzymes-dispersed covalent organic frameworks(COFs)as "organelle" to manage IBD.The Aprobiotics with the function of natural probiotics could markedly relieve the IBD by modulating the gut microbiota,suppressing intestinal inflammation,protecting the intestinal epithelial cells,and regulating immunity.This nature-inspired approach may aid to design more artificial systems for the treatment of various incurable diseases.