The Construction Of Erythrocyte Membrane Biomimetic Nano Drug-loaded Delivery System And Its Application In Synergistic Therapy

Although there are a lot of researches about cancer treatment,there are always shortcomings in chemotherapy and radiotherapy,such as incomplete treatment leading to postoperative recurrence,toxic side effects and poor treatment effects.The drug delivery system（DDS）has largely solved the problem of large toxic and side effects.However,due to the nanocarrier synthesized in vitro,it is easy to cause an immune response in the body and to be eliminated owe to the capture of macrophages.In order to better enhance the effect of tumor treatment,it is particularly important to select drug carriers with good biocompatibility and novel treatment methods.In recent years,its excellent biocompatibility and low immunogenicity have made biofilm biomimetic technology widely used.Because cell membrane biomimetic cloaked NPs can prolong the circulation time in the body,they are more conducive to the accumulation of tumor cells through the EPR effect.It is an effective method to treat tumors.In this study,RBCM biomimetic nano drug-loaded system was constructed for synergistic chemo-chemodynamic therapy（CDT）.The nano delivery can avoid avoided capture by macrophages,which led to increased enrichment at the tumor via the EPR effect.It is expected to become a new method for the treatment of cancer.First,porous poly（lactic-co-glycolic acid）（PLGA）nanoparticles（p-PLGA NPs）were prepared by nanoprecipitation method,and subsequently polymerize Mn²⁺-doped polydopamine（PDA）layer coated p-PLGA under alkaline aerobic conditions to obtain Mn²⁺-p-PLGA/PDA NPs with core shell structure.Ultraviolet spectroscopy showed that the hydroxyl radicals（HO·）was produced by Mn²⁺catalyzed the Fenton-like reaction and endogenous H₂O₂,indicating that the nano delivery has the potential for chemodynamic therapy.In order to improve its biocompatibility and reduce immunogenicity,we subsequently developed RBCM biomimetic nano drug-loaded system.Firstly,Mn²⁺-CP@p-PLGA/PDA NPs were prepared.These were subsequently coated with RBCM to obtain RBCM-Mn²⁺-CP@p-PLGA/PDA NPs.TEM showed that nano delivery was spherical,with a hydrodynamic diameter of 184.4±4 nm,and could stably exist in water and PBS.This particle size could be targeted to the tumor site through the EPR effect.Western blotting test results showed that the RMCM-coated NPs retained CD47（immunomodulation protein）,which could interact with the protein on the surface of macrophages to avoid being eliminated.The encapsulation rate and drug loading rate of CP were 85.3±1.2%and6.2±0.8%by UV spectrophotometer,respectively.The results of in vitro drug release experiments showed that the RMCM-coated NPs had a certain sustained effect and released more drugs under acidic conditions.In in vitro cell experiments,the results of MTT and cell live-dead staining experiments showed that RBCM-p-PLGA/PDA NPs and RBCM-Mn²⁺-p-PLGA/PDA NPs have good biocompatibility.,RBCM-Mn²⁺-CP@p-PLGA/PDA NPs could inhibit the growth of cancer cells through synergistic treatment compared with single treatment.RBCM-Mn²⁺-CP@p-PLGA/PDA NPs produced the most HO·in cancer cells by an inverted fluorescent microscope,indicating that cisplatin can not only exert chemotherapy effects,but also enhance CDT.The results of CLSM and flow cytometry showed that RBCM coating allows the NPs to be selectively taken up by cancerous cells and to evade phagocytosis by cells of immunity.The results of in vivo animal experiments showed that the RMCM-coated NPs had low toxic effect on the main organs of mice,and effectively inhibited the growth of tumor due to combination of chemotherapy and chemodynamic therapy to achieve the excellent therapeutic effect.In summary,the RBCM biomimetic nano drug-loaded system constructed in this study has low immunogenicity and good biocompatibility.While it could avoid being captured by macrophages through EPR effect for synergistic therapy to inhibit effectively the growth of the tumor.It shows that the RBCM biomimetic nano drug-loaded system has certain prospects in cancer treatment.