Metal-Polyphenol Nanovaccine For Cancer Immunotherapy And Anti-inflammatory Effects Of Polydopamine Nanoparticles Doped With Arginine

Cancer has been considered as a life-threatening illness.Cancer treatment include chemotherapy,radiotherapy and surgery.However,but drug resistance and the side effects are key reasons to account for unsuccessful cancer therapy.Cancer immunotherapy helps the host immune system to fight cancer and shows great potential in the treatment and prevention of cancer recurrence.Therapeutic tumor vaccines are an important part of tumor immunotherapy.Recent years,although rapid progress has been made in traditional tumor vaccines,the inability of the vaccine to be effectively transported to the draining lymph nodes and immune tolerance have decreased the efficacy of tumor vaccines.The introduction of nanotechnology provides an opportunity to improve and solve these problems.Compared with traditional tumor vaccines,nanovaccines have the advantages of higher antigen loading,stability and good targeting.However,the low bio-safety of nanovaccine and the weak antigen-specific immune response limit their application in clinic.Therefore,there is an urgent need to develop safe and efficient nanovaccine with low-cost.Metal-phenolic Networks(MPN)are polymer network structures formed by the coordination of polyphenol ligands and metal ions,which have good biocompatibility and versatility.MPN can form coatings on various templates to realize the functional modification of template materials.MPN-coated nanomaterials have strong interactions with biological macromolecules such as proteins and nucleic acids,which are conducive for the loading of antigens;MPN is responsive to pH stimulation and can promote antigen lysosomal escape and cytoplasm delivery;and it has the characteristics of low toxicity,easy preparation and low cost.Using MPN as a vaccine carrier can improve the safety of the vaccine and realize large-scale production.Based on this,the first part of this work focused on the assembly of MPN nanovaccine and their application in cancer immunotherapy.The mesoporous silica nanoparticles were as the substrate to adsorb mode antigen chicken ovalbumin OVA electrostatically,and the surface is coated with MPN coordinated with plant polyphenol tannic acid(TA)and FeⅢ,which could enhance the lysosomal escape of the nanovaccine.The surface is further modified with the targeting molecule mannose was also conjugated to the vaccine to enhance the vaccine uptake by the immune cells and improve the delivery efficiency.Finally,we got the nanovaccine named MS@OVA@MPN@Man.We found that the nanovaccine has good biocompatibility and higher cellular uptake by bone marrow-derived dendritic cells(BMDCs).Moreover,the nanovaccine could promote the antigen escape from lysosomes,enhance the expression of cell surface markers CD 8 6 and CD40 on BMDCs,and eventually increase the maturation of BMDCs.In vivo research showed that nanovaccines could promote the activation of dendritic cells(DCs)in lymph nodes and the proliferation of T cells in spleen and the T-cell infiltration into tumors,inhibiting tumor growth of in miceDopamine has a similar molecular structure to that of 2-hydroxy-phenylalanine(DOPA).It could deposit on most types of materials forming a film with controllable thickness and long-lasting stability.Therefore,it has been widely used as a new coating material in the field of biomedicine.With the anti-inflammatory properties,polydopamine nanoparticles are often used as carriers for the delivery of anti-inflammatory drugs.However,the polymerization of dopamine often led to a compact structure of polydopamine nanoparticles,which limits its anti-inflammatory effect.Therefore,in order to improve its anti-inflammatory effect,we prepared polydopamine nanoparticles doped with arginine to increase the loose structure and its anti-inflammatory effect.We investigated the anti-inflammatory effects of polydopamine nanoparticles in RAW264.7 cells in the absence and presence of LPS.The results showed that,compared with pure polydopamine nanoparticles,polydopamine nanoparticles doped with arginine could decrease the expression of pro-inflammatory related genes induced by LPS,including IL-6 and IL-1β,TNF-α,iNOS,but increase the expression of anti-inflammatory related genes including IL-10,TGF-β and HO-1.These results provide theoretical guidance for the application of polydopamine nanoparticles in inflammatory-related diseases.