Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(...Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(MMP13).Herein,we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable,cyanine 5(Cy5)-containing PEG,black hole quencher-3(BHQ3),and cRGD ligands and loaded with siRNA silencing MMP13(siM13),namely ERMs@siM13.ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell,causing cRGD exposure.Accordingly,the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surfaceαvβ3 integrin,increasing intracellular siM13 delivery for on-demand MMP13 downregulation.Meanwhile,the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle,precisely reflecting the diseased cartilage state.In particular,the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity,enabling the physicians to adjust the therapeutic regimen.Finally,in the murine PTOA model,ERMs@siM13 could diagnose the early-stage PTOA,perform timely interventions,and monitor the OA progression level during treatment through a real-time detection of MMP13.Therefore,ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.展开更多
In the rapidly advancing field of biomedical research,organoid technology has been a groundbreaking development.Organoids-three-dimensional structures derived from stem cells that replicate key structural and function...In the rapidly advancing field of biomedical research,organoid technology has been a groundbreaking development.Organoids-three-dimensional structures derived from stem cells that replicate key structural and functional features of human tissues-have transformed approaches to disease modelling,1 drug discovery,2 and regenerative medicine.3 With the ability to mimic human organs more accurately than traditional cell cultures or animal models,organoids offer tremendous potential for advancing precision medicine and personalised therapies.展开更多
基金supported by Integrated Project of Major Research Plan of National Natural Science Foundation of China (92249303)National Natural Science Foundation of China (82230071,82172098,82371603,82102217,81872428,and 81703010)+7 种基金the Shanghai Rising Star Program (21QA1412000)Shanghai Hospital Development Center (SHDC2023CRT013)Shanghai Committee of Science and Technology (23141900600,Laboratory Animal Research Project)Shanghai Baoshan District Medical Health Project (21-E-14)the Construction of Key Medical Disciplines of Baoshan District of Shanghai (BSZK-2023-Z07)the Shanghai Municipal Natural Science Foundation (23ZR1463300)Postdoctoral Fellowship Program of CPSF (GZB20230397)General Funding for China Postdoctoral Science Foundation (2023M732179).
文摘Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(MMP13).Herein,we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable,cyanine 5(Cy5)-containing PEG,black hole quencher-3(BHQ3),and cRGD ligands and loaded with siRNA silencing MMP13(siM13),namely ERMs@siM13.ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell,causing cRGD exposure.Accordingly,the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surfaceαvβ3 integrin,increasing intracellular siM13 delivery for on-demand MMP13 downregulation.Meanwhile,the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle,precisely reflecting the diseased cartilage state.In particular,the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity,enabling the physicians to adjust the therapeutic regimen.Finally,in the murine PTOA model,ERMs@siM13 could diagnose the early-stage PTOA,perform timely interventions,and monitor the OA progression level during treatment through a real-time detection of MMP13.Therefore,ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.
文摘In the rapidly advancing field of biomedical research,organoid technology has been a groundbreaking development.Organoids-three-dimensional structures derived from stem cells that replicate key structural and functional features of human tissues-have transformed approaches to disease modelling,1 drug discovery,2 and regenerative medicine.3 With the ability to mimic human organs more accurately than traditional cell cultures or animal models,organoids offer tremendous potential for advancing precision medicine and personalised therapies.
