查看更多>>摘要：The different fate of liposomes among species has been discovered and mentioned in many studies,but the underlying mechanisms have not been explored.In the present work,we concentrated on the in vivo fate of PEGylated liposomes(sLip)in three commonly used species(mice,rats,and dogs).It was exhibited that the accelerated blood clearance(ABC)phenomenon and hypersensitivity in large an-imals(beagle dogs)were much more significant than that in rodents.We demonstrated that anti-PEG IgM(partially)and complement(mostly)determined the elimination of sLip and linked the distinct interspe-cies performances with the diverse complement capacity among species.Based on the data from animals and clinical patients,it was revealed that the fate of sLip in large animals was closer to that in humans,for the sufficient complement capacity could expose the potential adverse reactions caused by anti-PEG an-tibodies.Our results suggested that the distinctive interspecies performances of sLip were highly related to the physiological variabilities among species,which should not be overlooked in the innovation and translation of nanomedicines.
查看更多>>摘要：Osteoarthritis(OA)is a type of highly prevalent heterogeneous degenerative disease that leads to joint pain,deformity,the destruction of articular cartilage,and eventual disability.The current treatment strategies for OA often suffer from systemic side effects,poor anti-inflammatory efficacy,and persistent pain.To address these issues,we develop light-inducible nanomedicine that enables the co-delivery of anti-inflammatory drug(diacerein,DIA)and small interfering RNA(siRNA)targeting nerve growth factor(NGF)for pain relief to enhance the therapeutic efficacy of OA.The nanomedicine is based on poly(β-amino-ester)-coated gold nanocages(AuNCs),which is further incorporated with the phase-change material(lauric acid/stearic acid,LA/SA).Following intra-articular(IA)injection in vivo,the nanomedicine displays high degree of drug accumulation and retention in the joint lesion of OA mouse models.The photothermal effect,induced by AuNCs,not only promotes DIA and siRNA release,but also upregulates the expression of heat shock protein 70(HSP-70)to resist the apoptosis of chondro-cytes in the inflammatory condition.The internalization of both DIA and siRNA results in strong anti-inflammatory and pain-relieving effects,which greatly contribute to the joint repair of OA mice.This study offers a promising combination strategy for OA treatment.
查看更多>>摘要：Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microen-vironment,posing formidable challenges for effective treatment.The disease is characterized by an altered glucose metabolism in macrophages,specifically an increase in aerobic glycolysis,which is linked to heightened inflammatory responses.This suggests that targeting macrophage metabolism could offer a new therapeutic avenue.In this study,we developed an immunometabolic intervention using quercetin(Q)encapsulated in bioadhesive mesoporous polydopamine(Q@MPDA)to treat periodontitis.Our re-sults demonstrated that Q@MPDA could reprogram inflammatory macrophages to an anti-inflammatory phenotype(i.e.,from-M l-to-M2 repolarization).In a murine periodontitis model,locally administered Q@MPDA reduced the presence of inflammatory macrophages,and decreased the levels of inflammatory cytokines(IL-1β and TNF-α)and reactive oxygen species(ROS)in the periodontium.Consequently,it alleviated periodontitis symptoms,reduced alveolar bone loss,and promoted tissue repair.Furthermore,our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory mac-rophages while enhancing oxidative phosphorylation(OXPHOS),facilitating the shift from Ml to M2 macrophage subtype.Our findings suggest that Q@MPDA is a promising treatment for periodontitis via immunometabolic rewiring.
查看更多>>摘要：High glucose level,bacterial infection,and persistent inflammation within the microenviron-ment are key factors contributing to the delay of diabetic ulcers healing,while traditional therapeutic methods generally fail to address these issues simultaneously.Here,we present a spatiotemporally responsive cascade bilayer microneedle(MN)patch for accelerating diabetic wound healing via local glucose depletion and sustained nitric oxide(NO)release for long-term antibacterial and anti-inflammatory effects.The MN patch(G/AZ-MNs)possesses a degradable tip layer loading glucose ox-idase(GOx),as well as a dissolvable base layer encapsulating L-arginine(Arg)-loaded nanoparticles(NPs).After wound administration,the base part rapidly dissolved,resulting in prompt separation of the MN tip within the wound tissue,which subsequently responded to the overexpressed matrix metalloproteinase-9(MMP-9)in diabetic lesions,leading to the responsive release of GOx.The released enzyme catalyzed glucose into gluconic acid and hydrogen peroxide(H2O2),which not only reduced glucose level within the diabetic wound,but also initiated the cascade reaction between H2O2 with the Arg that was released from NPs,thereby achieving continuous production of NO for 7 days.Our findings demonstrate that a single administration of the MN patch could effectively heal non-infected or biofilm-infected diabetic wounds with the multifunctional properties.
查看更多>>摘要：Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug de-livery.However,it remains a challenge to localize and control drug release while retaining macrophage activity and exerting its immunotherapeutic effect.Herein,a localized light-triggered release macrophage cytopharmaceutical(USIP@M)was proposed,which could utilize the tumor targeting and immuno-therapy effects of macrophages to reverse the immune suppression of tumor microenvironment(TME).Amphiphilic block copolymers with ultraviolet(UV)-responsive o-nitrobenzyl groups were synthesized and co-loaded with sorafenib(SF),IMD-0354(IMD),and upconverting nanoparticles(UCNPs),which were then taken up by macrophages,and the targeted delivery of drugs was realized by using the tumor tropism of macrophages.UCNPs converted near-infrared light with strong penetrability and high safety into UV light,which promoted the photoresponsive depolymerization of block copolymers and produc-tion of exosomes from USIP@M,accelerated drug efflux and maintained the activity of macrophages.IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the anti-tumor effect of macrophages,enhance T cell immunity,and alleviate the immunosuppressive state of TME.Synergistically with the chemotherapeutic effect of SF,it could effectively kill tumors.In conclu-sion,based on the localized light-triggered release strategy,this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macro-phages and exerting its immunotherapeutic effect,which could effectively treat solid tumors.
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