Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi infection. Recently, the rapid increase of scrub typhus incidence in several countries within the endemic region has become a serious public health issue. Despite the wide range of preventative approaches that have been attempted in the past 70 years, all have failed to develop an effective prophylactic vaccine. Currently, the selection of the proper antigens is one of the critical barriers to generating cross-protective immunity against antigenically-variable strains of O. tsutsugamushi. We examined the potential role of ScaA protein, an autotransporter protein of O. tsutsugamushi, in bacterial pathogenesis and evaluated the protective attributes of ScaA immunization in lethal O. tsutsugamushi infection in mice. Our findings demonstrate that ScaA functions as a bacterial adhesion factor, and anti-ScaA antibody significantly neutralizes bacterial infection of host cells. In addition, immunization with ScaA not only provides protective immunity against lethal challenges with the homologous strain, but also confers significant protection against heterologous strains when combined with TSA56, a major outer membrane protein of O. tsutsugamushi. Immunization of ScaA proteins provides protective immunity in mice when challenged with the homologous strain and significantly enhanced protective immunity against infection with heterologous strains. To our knowledge, this is the most promising result of scrub typhus vaccination trials against infection of heterologous strains in mouse models thus far. Scrub typhus, caused by Orientia tsutsugamushi infection, is one of the common febrile illness in the Asia-Pacific region, accounting for up to 20% of febrile hospital admissions in rural areas of southern Asia. It has been estimated that one billion people are at risk and one million cases occur annually in the Asian-Pacific region. Despite continuous efforts to develop a vaccine against scrub typhus during the last several decades, all approaches have failed to induce effective immunity. The main issue for the development of a scrub typhus vaccine is the selection of proper antigens that cover a broad range of antigenic strains and induce long-lasting immunity. Here, we examined the potential use of ScaA protein as a vaccine antigen. Our findings demonstrate that ScaA protein functions as a bacterial adhesion factor and an antibody against ScaA significantly inhibits bacterial infection into host cells. In addition, ScaA vaccination provides protective immunity against lethal challenges of the homologous strain, and also confers better protection against heterologous strains when combined with TSA56, the major outer membrane protein that was previously used as a potential vaccine antigen. These results indicate that ScaA proteins could be used as a novel vaccine target for scrub typhus.

Engineering and application of nanomaterials have recently helped advance various biomedical fields. Zinc oxide (ZnO)-based nanocomposites have become one of the most promising candidates for biomedical applications due to their biocompatibility, unique physicochemical properties, and cost-effective mass production. In addition, recent advances in nano-engineering technologies enable the generation of ZnO nanocomposites with unique three-dimensional structures and surface characteristics that are optimally designed for in vivo applications. Here, we review recent advances in the application of diverse ZnO nanocomposites, with an especial focus on their development as vaccine adjuvant and cancer immunotherapeutics, as well as their intrinsic properties interacting with the immune system and potential toxic effect in vivo. Finally, we summarize promising proof-of-concept applications as prophylactic and therapeutic vaccines against infections and cancers. Understanding the nano-bio interfaces between ZnO-based nanocomposites and the immune system, together with bio-effective design of the nanomaterial using nano-architectonic technology, may open new avenues in expanding the biomedical application of ZnO nanocomposites as a novel vaccine platform.

Cancer immunotherapy has gained momentum for treating malignant tumors over the past decade. Checkpoint blockade and chimeric antigen receptor cell therapy (CAR-T) have shown considerable potency against liquid and solid cancers. However, the tumor microenvironment (TME) is highly immunosuppressive and hampers the effect of currently available cancer immunotherapies on overall treatment outcomes. Advancements in the design and engineering of nanomaterials have opened new avenues to modulate the TME. Progress in the current nanocomposite technology can overcome immunosuppression and trigger robust immunotherapeutic responses by integrating synergistic functions of different molecules. We will review recent advancements in nanomedical applications and discuss specifically designed nanocomposites modulating the TME for cancer immunotherapy. In addition, we provide information on the current landscape of clinical-stage nanocomposites for cancer immunotherapy.

Zinc oxide nanoparticle (ZNP) has been applied in various biomedical fields. Here, we investigated the usage of ZNP as an antigen carrier for vaccine development by combining a high affinity peptide to ZNP. A novel zinc oxide-binding peptide (ZBP), FPYPGGDA, with high affinity to ZNP (K a = 2.26 × 106 M−1) was isolated from a random peptide library and fused with a bacterial antigen, ScaA of Orientia tsutsugamushi, the causative agent of scrub typhus. The ZNP/ZBP-ScaA complex was efficiently phagocytosed by a dendritic cell line, DC2.4, in vitro and significantly enhanced anti-ScaA antibody responses in vivo compared to control groups. In addition, immunization with the ZNP/ZBP-ScaA complex promoted the generation of IFN-γ-secreting T cells in an antigen-dependent manner. Finally, we observed that ZNP/ZBP-ScaA immunization provided protective immunity against lethal challenge of O. tsutsugamushi, indicating that ZNP can be used as a potent adjuvant when complexed with ZBP-conjugated antigen. ZNPs possess good adjuvant potential as a vaccine carrier when combined with an antigen having a high affinity to ZNP. When complexed with ZBP-ScaA antigen, ZNPs could induce strong antibody responses as well as protective immunity against lethal challenges of O. tsutsugamushi. Therefore, application of ZNPs combined with a specific soluble antigen could be a promising strategy as a novel vaccine carrier system.

Zinc oxide (ZnO)-based nanocomposites have shown promising potential for various biomedical applications, including vaccine development, owing to their multifunctionality and biocompatibility. Here, we synthesized radially grown ZnO nanowires (NWs) on poly-L-lactic acid (PLLA) microfibers with unique 3-dimensional structure and applied them as therapeutic cancer vaccines. This inorganic–organic hybrid nanocomposite has mild cellular toxicity but efficiently delivers a tumor antigen into dendritic cells, cellular bridges between innate and adaptive immunity, to stimulate them to express inflammatory cytokines and activation surface markers. We also demonstrated that the hybrid nanocomposites successfully induce tumor antigen-specific cellular immunity and significantly inhibit tumor growth in vivo. ZnO NWs on PLLA fibers systemically reduced immune suppressive T_Reg cells and enhanced the infiltration of T cells into tumor tissues, compared to mice immunized with PLLA fibers coated with the antigen. Our current findings open a new avenue in extending the biomedical application of inorganic metal oxide-inert organic hybrid nanocomposites as a novel vaccine platform.