Experimental Study Of Vascular Bursts Mediated By AuNPs-CpG To Promote Tumor Radio-Immunotherapy

Object:Although nanomedicines have made significant progress in basic research and clinical translation of tumor therapy,debates about their tumor targeting and intratumoral penetration efficiency persist.We are committed to the precise control of the spatiotemporal delivery of nanomedicines by modulating the tumor microenvironment through radiotherapy.Methods: We employed a strategy of two low-dose radiotherapy to achieve significant accumulation and deep penetration of spherical nucleic acid(SNA)-based nanomedicines for synergistic radioimmunotherapy.The first RT was used to recruit large numbers of macrophages into tumors.Tumor-infiltrating macrophages not only serve as nanoparticle drug depots,but also trigger dynamic burst extravasation to enhance nanoparticle accumulation in tumor areas.A second RT was then administered to sensitize and reshape the tumor immune microenvironment,leading to a synergistic anti-cancer adaptive immune response in combination with an anti-PD-L1 antibody(αPD-L1).Results: We optimized the spatiotemporal combination of RT and SNA to Achieving higher levels of SNA delivery,the delivered SNA can further promote the M2 to M1 phenotype switch of macrophages,after the switch,the ability to phagocytose SNA is increased by 6-fold,resulting in a positive feedback of tumor penetration of SNA,reaching its role in the tumor.deep infiltration and accumulation.This RTmediated burst of blood vessels can increase the delivery efficiency of nanoparticles by 25-fold.SNAs ultimately distributed in tumors simultaneously sensitize a second dose of RT and remodel the tumor immune microenvironment,resulting in a synergistic anticancer adaptive immune response in combination with an anti-PD-L1 antibody(αPD-L1),whereas both RT and None of αPD-L1 caused significant side effects.Conclusions: We propose a highly robust strategy for tumortargeted delivery of nanomedicines by combining low-dose RT and Au NPs-CpG for synergistic radioimmunotherapy,and provide a promising strategy for anti-tumor by synergistic radioimmunotherapy.