Vascular Bursts-Mediated Tumor Accumulation and Deep Penetration of Spherical Nucleic Acids for Synergistic Radio-Immunotherapy.

While nanomedicines have attracted great interests for tumor therapy, their targeting and intra-tumoral penetrating efficiencies have been questioned. Here, we report a two-step low-dose radiotherapy (RT) strategy to realize significant accumulation and deep penetration of spherical nucleic acids (SNAs)-based nanomedicine for synergistic radio-immunotherapy. The first step RT was employed to recruit large amounts of macrophages into tumor. The tumor infiltrated macrophages not only served as nanoparticles drug depots, but also elicited dynamic bursts extravasation to enhance nanoparticles accumulation. We optimized the spatiotemporal combination of RT and SNAs administration for higher level of SNAs delivery, and the delivered SNAs promote M2-to-M1 phenotype switch of macrophages to increase phagocytosis of nanoparticles by 6-fold, resulting in positive feedback with even higher accumulation and intra-tumor penetration of SNAs. Through vascular bursts and macrophage repolarization, as high as 25-fold enhancement of nanoparticles accumulation was achieved as compared to passive targeting of nanoparticles, and the nanoparticles were eventually distributed throughout the tumor tissue with efficient deep penetration. Finally, SNAs in tumor simultaneously sensitized the second dose of RT and remodeled tumor immune microenvironment, resulting in a synergistic anticancer therapy in combination of anti-PD-L1 antibody (αPD-L1) with no noticeable side effects caused by either RT or αPD-L1.