Liposomalα-cyperone targeting bone resorption surfaces suppresses osteoclast differentiation and osteoporosis progression via the PI3K/Akt axis

Osteoporosis is a metabolic dysregulation of bone that occurs mainly in postmenopausal women,and the hyperfunction of osteoclasts is the primary contributor to postmenopausal osteoporosis.However,the development of effective therapeutic drugs and precise delivery systems remains a challenge in the field of anti-absorption therapy.Here,we reported theα-cyperone(α-CYP)for anti-osteoporosis and developed a liposome-based nano-drug delivery system ofα-CYP,that specifically targets the bone resorption interface.Firstly,we found that theα-CYP,one of the major sesquiterpenes of Cyperus rotundus L.,attenuated the progression of osteoporosis in ovariectomized(OVX)mice and down-regulated the expression of phosphorylated proteins of phosphoinositide 3-kinase(PI3K)and protein kinase B(Akt),causing down-regulation of osteoclast-related genes/proteins and curbing osteoclast differentiation.Furthermore,α-CYP reversed the activation of osteoclastic differentiation and enhanced osteoporosis-related proteins expression caused by PI3K/Akt agonist(YS-49).More importantly,we adopted the osteoclastic resorption surface targeting peptide Asp8 and constructed the liposome(lipαC@Asp8)to deliverα-CYP to osteoclasts and confirmed its anti-osteoporosis effect and enhanced osteoclast inhibition by blocking PI3K/Akt axis.In conclusion,this study demonstrated thatα-CYP inhibits osteoclast differentiation and osteoporosis development by silencing PI3K/Akt pathway,and the liposome targeting delivery systems loaded withα-CYP might provide a novel and effective strategy to treat osteoporosis.

Microalgae-based drug delivery system for tumor microenvironment photo-modulating and synergistic chemo-photodynamic therapy of osteosarcoma

Osteosarcoma(OS)is one of the most common malignant tumors in children and young adults.As chemotherapy and other therapies are limited by low therapeutic efficiency,severe side effects and single therapeutic function,it is of high value to develop innovative therapies for precise and efficient treatment of OS.Herein,natural photo-synthetic microalgae(C.vulgaris,CV)were utilized as carriers for the chemotherapeutic agent doxorubicin(DOX)to create a multifunctional therapeutic platform(CV@DOX)for the photo-modulation of the tumor microenvi-ronment(TME)and synergistic chemo-photodynamic therapy of osteosarcoma.CV@DOX exhibited rapid drug release behavior in the acidic TME,improving the efficiency of chemotherapy against tumors and reducing side effects on other normal tissues.Under 650 nm laser irradiation,CV@DOX demonstrated the ability to effectively generate oxygen to alleviate tumor hypoxia and utilize the photosensitizing properties of chlorophyll in CV to produce an increased amount of reactive oxygen species(ROS),thereby enhancing photodynamic therapy(PDT).CV@DOX-mediated synergistic chemo-photodynamic therapy demonstrated efficacy in halting tumor progression in an orthotopic osteosarcoma mouse model by promoting tumor cell apoptosis,inhibiting tumor proliferation and angiogenesis.Moreover,chlorophyll-assisted fluorescence imaging enabled monitoring of the distribution of CV@DOX in osteosarcoma after administration.Finally,CV@DOX did not cause significant hematological and tissue toxicity,and prevented DOX-induced cardiotoxicity,showing good in vivo biocompatibility.Overall,this work presents a novel TME-responsive and TME-modulating platform for imaging-guided multimodal osteosar-coma treatment.