Application Of Metal-Based Stimuli-Responsive Nanomaterials Represented By Zinc And Magnesium In Deep Tissue-Related Diseases

Metal-based nanomaterials are favored by many researchers because of their multi-functionality,which are widely studied in various fields of biomedicine,including biosensing,bioimaging,anti-cancer,anti-infection and tissue repair.Currently,the design of intelligent treatment systems based on stimuli-responsive metal-based nanomaterials has become a hot topic and focus of research.Herein,taking the therapy of deep tissue-related diseases(subcutaneous fungal infection and osteoporosis)as an example,we designed and constructed metal-based stimuliresponsive nanoplatforms represented by zinc and magnesium.A series of their physicochemical properties and biosafety were systematically explored,and finally,their anti-fungal,healing-promoting,inflammation-regulating and anti-osteoporosis effects were verified in animal models.All the main research contents of this study are summarized as follows:(1)Fungal infection possesses the characteristics of high invasion depth and easy formation of a biofilm under the skin,which greatly hinders the treatment process.Here,traditional Chinese medicine moxa was carbonized and modified with zinc oxide(ZnO)nanosheets to synthesize carbonized moxa@ZnO(CMZ)with the dual response properties of yellow light(YL)and ultrasound(US)for synergistic antifungal therapy.CMZ with a narrow bandgap could respond to long-wavelength YL that was highly safe and helpful for skin repair.Simultaneously,CMZ with a piezoelectric effect could further enhance the photocatalytic efficiency under the stimulation of US with high tissue penetration.Genomic investigation indicated that when exposed to US and YL irradiation,CMZ-based therapy could adjust the expression of genes associated with fungal virulence,metabolic activity,mycelial growth and biofilm development,thus efficaciously eradicating planktonic Candida albicans(C.albicans)and mature biofilm.Importantly,despite the 1.00 cm thick tissue barrier,CMZ could rapidly eliminate 99.9%of C.albicans within 4 min,showing satisfactory deep fungicidal efficacy.The in vivo therapeutic effect of CMZ-based antifungal strategy was demonstrated in both open wound and deep cutaneous infection models,speaking of dramatically better efficacy than the traditional fungicide ketoconazole.(2)Osteoporosis is the most common bone metabolic disease that affects the health of middle-aged and elderly people,which is hallmarked by imbalanced bone remodeling and a deteriorating immune microenvironment.Magnesium and calcium are pivotal matrix components that participate in the bone formation process,especially in the immune microenvironment regulation and bone remodeling stages.Nevertheless,how to potently deliver magnesium and calcium to bone tissue remains a challenge.Here,we constructed a multifunctional nanoplatform(CM-NH2-PAA-Ald,CMPA)composed of calcium-based upconversion nanoparticles and magnesium organic frameworks,which featured bone-targeting and pH-responsive properties,effectively regulating the inflammatory microenvironment and promoting the coordination of osteogenic functions for treating osteoporosis.CMPA could efficaciously target bone tissue and gradually degrade in response to the acidic microenvironment of osteoporosis to release magnesium and calcium ions.In vitro and in vivo experiments validated that CMPA with favorable biocompatibility could suppress inflammation and facilitate osteogenesis to treat osteoporosis.Importantly,high-throughput sequencing results demonstrated that the nanoplatform exerted a good inflammatory regulation effect through inhibition of the nuclear factor kappa-B signaling pathway,thereby regulating the osteoporotic microenvironment.This collaborative therapeutic strategy that focuses on improving bone microenvironment and promoting osteogenesis provides new insight for the treatment of metabolic diseases such as osteoporosis.