Reactive Oxygen Species-Sensitive Biodegradable Mesoporous Silica Nanoparticles Harboring TheraVac Elicit Tumor-Specific Immunity for Colon Tumor Treatment.

Abstract

Immunotherapy has revolutionized the field of cancer treatment through invigorating robust antitumor immune response. Here, we report the development of a <b>thera</b>peutic <b>vac</b>cine [consisting of high mobility group nucleosome-binding protein 1 (HMGN1), resiquimod/R848, and anti-PD-L1 (αPD-L1)]-loaded reactive oxygen species (ROS)-responsive <b>m</b>esoporous <b>s</b>ilica <b>n</b>anoparticle (<b>MSN@TheraVac</b>) for curative therapy of colon cancer. In MSN@TheraVac, αPD-L1 conjugated onto the surface of MSNs via a diselenide bond, which can be rapidly released under the oxidative condition of the tumor microenvironment to avert immunosuppression and effector T cell exhaustion while coloaded HMGN1 and R848 would cooperatively trigger robust tumor-infiltrating dendritic cell (TiDC) maturation and elicitation of antitumor immune responses. Indeed, MSN@TheraVac induced the maturation and activation of dendritic cells (DCs) by promoting the surface expression of CD80, CD86, and CD103 as well as the production of pro-inflammatory cytokines, including TNFα, IL-12, and IL-1β. Importantly, treatment with intravenous MSN@TheraVac led to a complete cure of 100% of BALB/c mice bearing large colon tumors and induced the generation of tumor-specific protective memory without apparent toxicity. Thus, MSN@TheraVac provides a timely release of TheraVac for the curative treatment of colon tumors and holds potential for translation into a clinical therapy for patients with immunologically "cold" colorectal cancers. This ROS-responsive MSN platform may also be tailored for the selective delivery of other cancer vaccines for effective immunotherapy.