Bacteria-like tumor vaccines progressively initiate cascade reaction for precise antigen delivery and induction of anti-tumor cellular immune response

Abstract

In the field of anti-tumor immunotherapy, tumor vaccines gained more and more attention due to their unique advantages. The overall effectiveness of tumor vaccines is determined by the strength of the induced anti-tumor cellular immune response, which further depends on the several key steps (similar to a cascade reaction) during the whole immune response elicited by tumor vaccines. However, the design to fulfill every key step varies to a certain degree and sometimes even conflicts, usually leading to compromised vaccination effectiveness due to one or more rate-limiting steps. In this work, bacteria-like tumor vaccines with cascade reaction properties were elaborately designed to precisely aim to all the key steps of the whole immune cascade. For this purpose, the tumor vaccines were prepared by a simple layer-by-layer (LBL) self-assembly of positive-charged CpG-grafted disulfide-bond-bearing hyperbranched poly(amido amine) (HPAA-CpG) and negative charged model antigen ovalbumin (OVA) on CaCO3 nanoparticles to form the biodegradable CaCO3@(OVA/HPAA-CpG)3 vaccines. Benefiting from the cascaded properties, the vaccines could effectively load the antigen in a LBL manner, efficiently activate and enter antigen presenting cells by rational characteristics (size, morphology and PAMPs presentation), escape the lysosomes through bubbles explosive force, and approximate zero-order release the antigen into cytoplasm by virtue of LBL HPAA degradation to induce potent and continuous anti-tumor cellular immune response. The preventive and therapeutic animal tests prove the promising anti-tumor effectiveness of the vaccines. The design strategy raised in this study provides a novel view for the development of effective tumor vaccines.