A chemoimmunotherapy-based strategy to enhance tumor therapy by cross-linking a novel size-variable nanocluster via a bifunctional peptide

The combination of chemotherapy and immunotherapy plays a synergistic role in improving the effectiveness of cancer treatment. However, it is a great challenge to deliver drugs accurately and efficiently to the target and exert synergistic effects due to multiple biological obstacles in vivo. Here, we constructed a novel size-variable three-dimensional mesh nanocluster (HA/P-A cluster) cross-linked by bifunctional peptide R14 for tumor targeted co-delivery of doxorubicin (DOX) and pPD-L1 trap. The ERP effect and the targeting effect of the outer layer of HA synergistically mediated the accumulation of nanoclusters in tumor tissues. Subsequently, R14 was broken by matrix metalloproteinase-2 (MMP-2) and the nanoclusters (180 nm) were cleaved into ultra-small size nanoparticles (∼10 nm), achieving deep penetration while targeting tumor cells through RGD at both ends of R14. Based on this strategy, DOX acts as an initiator to induce immunogenic cell death (ICD) while immunodrugs block the PD-L1 pathway. Both in vitro and in vivo studies have shown that HA/P-A cluster effectively retarded tumor growth. Moreover, HA/P-A cluster treatment resulted in a significant increased CD8+ T cell infiltration in tumor tissue. In conclusion, this strategy provides a new direction for targeted co-delivery of nanoplatforms to improve chemoimmunotherapy in solid tumors.