Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy

Osteosarcoma is usually resistant to immunotherapy and,thus primarily relies on surgical resection and high-dosage chemotherapy.Unfortunately,less invasive or toxic therapies such as photothermal therapy(PTT)and chemodynamic therapy(CDT)generally failed to show satisfactory outcomes.Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma.Herein,a simple nanocomposite that synergistically combines CDT,PTT,and chemotherapy for osteosarcoma treatment was fabricated.In this composite,small 2D Ni Fe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil(5-FU)with high loading capacity.The nanospheres were then adsorbed onto larger 2D Ti3C2MXene monolayers and finally shielded by bovine serum albumin(BSA)to form 5-FU@Ni Fe-LDH/Ti3C2/BSA nanoplatforms(5NiTiB).Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy,Ni Fe-LDH driven chemodynamic effects,and MXene-based photothermal killing collectively exhibited a synergistic“all-in-one”anti-tumor effect.5NiTiB improved tumor suppression rate from<5%by 5-FU alone to~80.1%.This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose,thereby minimizing side effects.Moreover,the composite is simple to produce,enabling the fine-tuning of dosages to suit different requirements.Thus,the platform is versatile and efficient,with potential for further development.

Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms

Rheumatoid arthritis(RA)is a common chronic inflammatory disorder that usually affects joints.It was found that roburic acid(RBA),an ingredient from anti-RA herb Gentiana macrophylla Pall.,displayed strong anti-inflammatory activity.However,its medical application is limited by its hydrophobicity,lack of targeting capability and unclear functional mechanism.Here,we constructed a pH responsive dual-target drug delivery system hitchhiking RBA(RBA-NPs)that targeted both CD44 and folate receptors,and investigated its pharmacological mechanism.In rat RA model,the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA,as well as strongly reducing inflammatory cytokine levels and promoting tissue repair.Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA.Since the balance of pro-and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA,this reprogramming is likely responsible for the anti-RA effect.Furthermore,we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway.Thus,our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA,but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation.