Interstitial hypertension and extracellular matrix(ECM)barriers imposed by cancer-associated fibroblasts(CAFs)at the tumor site significantly impede the retention of intratumorally administered oncolytic viruses(OVs)a...Interstitial hypertension and extracellular matrix(ECM)barriers imposed by cancer-associated fibroblasts(CAFs)at the tumor site significantly impede the retention of intratumorally administered oncolytic viruses(OVs)as well as their efficacy in infecting and eradicating tumor cells.Herein,a stable,controllable,and easily prepared hydrogel was developed for employing a differential release strategy to deliver OVs.The oncolytic herpes simplex virus-2(oH2)particles were loaded within sodium alginate(ALG),together with the small molecule drug PT-100 targeting CAFs.The rapid release of PT-100 functions as an anti-CAFs agent,reducing ECM,and alleviating interstitial pressure at the tumor site.Consequently,the delayed release of oH2 could more effectively invade and eradicate tumor cells while also facilitating enhanced infiltration of immune cells into the tumor microenvironment,thereby establishing an immunologically favorable milieu against tumors.This approach holds significant potential for achieving highly efficient oncolytic virus therapy with minimal toxicity,particularly in tumors rich in stromal components.展开更多
Chronic inflammation is critical in the onset and progression of atherosclerosis(AS).The lipopolysaccharide(LPS)level in the circulation system is elevated in AS patients and animal models,which is correlated with the...Chronic inflammation is critical in the onset and progression of atherosclerosis(AS).The lipopolysaccharide(LPS)level in the circulation system is elevated in AS patients and animal models,which is correlated with the severity of AS.Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype,aggravate inflammation,and ultimately contribute to the exacerbation of AS,LPS in the circulation system was supposed to be the therapeutic target for AS treatment.In the present study,polymyxin(PMB)covalently conjugated to PEGylated liposomes(PLPs)were formulated to adsorb LPS through specific interactions between PMB and LPS.In vitro,the experiments demonstrated that PLPs could adsorb LPS,reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells.In vivo,the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines,decreased the proportion of M1-type macrophages in AS plaque,stabilized AS plaque,and downsized the plaque burdens in arteries,which eventually attenuated the progression of AS.Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.展开更多
基金supported by the National Key R&D Program of China(No.2022YFC2403401)the National Natural Science Foundation of China(Nos.82073368,82303766)+2 种基金the Liaoning Revitalization Talents Program(No.XLYC2007071)the China Postdoctoral Science Foundation(No.2023M743908)the Joint Program of Science and Technology Program of Liaoning Province(No.2023JH2/101700094).
文摘Interstitial hypertension and extracellular matrix(ECM)barriers imposed by cancer-associated fibroblasts(CAFs)at the tumor site significantly impede the retention of intratumorally administered oncolytic viruses(OVs)as well as their efficacy in infecting and eradicating tumor cells.Herein,a stable,controllable,and easily prepared hydrogel was developed for employing a differential release strategy to deliver OVs.The oncolytic herpes simplex virus-2(oH2)particles were loaded within sodium alginate(ALG),together with the small molecule drug PT-100 targeting CAFs.The rapid release of PT-100 functions as an anti-CAFs agent,reducing ECM,and alleviating interstitial pressure at the tumor site.Consequently,the delayed release of oH2 could more effectively invade and eradicate tumor cells while also facilitating enhanced infiltration of immune cells into the tumor microenvironment,thereby establishing an immunologically favorable milieu against tumors.This approach holds significant potential for achieving highly efficient oncolytic virus therapy with minimal toxicity,particularly in tumors rich in stromal components.
基金supported by the National Natural Science Foundation of China(82070228,81773283)the National Key R&D Program of China(No.2019YFC1316204)。
文摘Chronic inflammation is critical in the onset and progression of atherosclerosis(AS).The lipopolysaccharide(LPS)level in the circulation system is elevated in AS patients and animal models,which is correlated with the severity of AS.Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype,aggravate inflammation,and ultimately contribute to the exacerbation of AS,LPS in the circulation system was supposed to be the therapeutic target for AS treatment.In the present study,polymyxin(PMB)covalently conjugated to PEGylated liposomes(PLPs)were formulated to adsorb LPS through specific interactions between PMB and LPS.In vitro,the experiments demonstrated that PLPs could adsorb LPS,reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells.In vivo,the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines,decreased the proportion of M1-type macrophages in AS plaque,stabilized AS plaque,and downsized the plaque burdens in arteries,which eventually attenuated the progression of AS.Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.
