Biomimetic nano-in-gel vaccine platform with spatiotemporal co-delivery capacity for DC maturation against immunosuppressive tumors

Abstract

Therapeutic tumor vaccinations are promising for cancer immunotherapy. However, challenges like inadequate antigen encapsulation, weak immune activation, and an immunosuppressive tumor microenvironment limit their efficacy. To overcome these, an injectable Nano-in-Gel vaccine composed of porcine lung-derived extracellular matrix hydrogel (ECMG), tumor cell lysate (TCL), Poly I:C, and PD-L1 siRNA-loaded lipid nanoparticles (LNP) was developed. The ECMG derived from lung loose connective tissue exhibits excellent biocompatibility and degradability. It mimics the mechanical stress environment of natural ECM and contains bioactive components such as proteins, peptides, and polysaccharides. Administration of two weekly doses efficiently facilitated the transport of antigens and adjuvants to dendritic cells (DCs), thereby inducing robust immune responses and promoting dendritic cell maturation within lymph nodes. Importantly, PD-L1 siRNA-loaded LNPs reduced immunosuppressive signals in mature DCs, enhancing T-cell production and infiltration while alleviating the immunosuppressive tumor environment. The hydrogel scaffold achieves sustained antigen presentation and TLR3 activation through the sustained delivery of TCL and Poly I:C, while the targeted delivery characteristics of LNPs ensure the precise silencing of the immune checkpoint PD-L1 by siRNA. Overall, this study offers a proof-of-concept for a more efficient dendritic cell (DC)-activating strategy that integrates natural hydrogel scaffolds, whole tumor cell vaccines, and immune checkpoint inhibitors.