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With rapid developments in medical science and technology, vaccination has become the key to solving public health problems. Various diseases can be prevented by vaccination, which mimic a disease by using a small part of the causal organism-also called an antigen-to stimulate the specific immune response to defend the host against the disease. The interaction between antigens and antigen-presenting cells (APCs) affects the efficacy of a vaccine. Adjuvants are crucial components of vaccines, optimizing the process of antigen phagocytosis by the APCs to some extent. However, many vaccinations fail during application in clinical trials owing to drawbacks of some antigens and adjuvants, such as immunogenicity and high degradability. Owing to rapid developments in the payload, targeted delivery and controllable release of drug delivery systems, they may have the potential to improve vaccines. In our review, we discuss multiple delivery systems and their role in vaccines and discuss how the major physical properties of delivery systems ultimately affect the success of vaccines, such as size, morphology, surface charge and elasticity.

Effective systemic therapy is often necessary to treat hepatocellular carcinoma (HCC). We synthesized a Gal-PPE nanogel consisting of a cross-linked polyphosphate core and galactosylated poly(ethylene glycol) arms for enhanced doxorubicin delivery to diethylnitrosamine-induced HCC in rats. The Gal-PPE nanogel exhibited high affinity to HepG2 cells in vitro, mediated by the asialoglycoprotein receptor. In vivo studies revealed that the Gal-PPE nanogel was taken up more efficiently by hepatocytes, in contrast to m-PPE nanogel. Consequently, doxorubicin delivery with Gal-PPE significantly inhibited the progress of HCC, reducing neoplastic liver nodules and prolonging the survival time of HCC rats more significantly. These results demonstrate the potential of Gal-PPE as a nanocarrier for improved HCC chemotherapy.

Macrophage-targeted drug delivery has great therapeutic potential for the treatment of cancers and inflammatory diseases. There is also an unmet need for efficient and nontoxic means of in vivo macrophage depletion to determine the role of macrophages under normal and disease settings. Herein, we explored the potential of red blood cell (RBC)-derived nanovesicles (RDNVs) as drug nanocarriers to specifically deplete macrophages. We show that RDNVs are effective hydrophilic drug carriers and can effectively deliver drugs into macrophages both in vitro and in vivo. Nanovesicles derived from both wild-type mouse RBCs (WT-RDNVs) and CD47 KO mouse RBCs (KO-RDNVs) can encapsulate clodronate with good stability in PBS for long-term storage. However, KO-RDNVs were more efficiently engulfed by macrophages in vitro and more rapidly cleared in vivo than WT-RDNVs, indicating that CD47 also serves as a "don't eat me" molecule for RDNVs as it does for RBCs. Accordingly, clodronate-encapsulated KO-RDNVs (KO-RDNV/CLD) were significantly more toxic to mouse macrophages in vitro than drug-loaded WT-RDNVs (WT-RDNV/CLD). Furthermore, WT-RDNV/CLD showed prolonged accumulation in tissues (e.g., liver and lung) and macrophage depletion versus KO-RDNV/CLD. Importantly, RBC-derived nanovesicles are more biocompatible and less toxic in vivo than clodronate-encapsulated liposomes-the current gold-standard macrophage-depleting reagent. This study offers a useful strategy for macrophage-targeted drug delivery.

Immunotherapy has shown promising results in multiple malignancies. However, there are still significant challenges in cancer immunotherapy including the powerful immunosuppressive tumor microenvironment and adverse off-target side effects. Nanomaterials with defined physico-biochemical properties are versatile drug delivery platforms that may address these key technical challenges faced by cancer immunotherapy. Here, a tumor acidity-responsive biomacromolecule delivery system was designed to intratumorally deliver an immune-activating cytokine, macrophage colony-stimulating factor (M-CSF) and attenuate the acidic microenvironment. This nanoparticle was prepared by introducing CaCO3 as a crosslinker to form an M-CSF-loaded stable micelle (NP/M-CSF/CaCO3). Administration of NP/M-CSF/CaCO3 significantly inhibited tumor growth by enhancing T cell-mediated anti-tumor immune responses and reversing the TAM-mediated immunosuppression. This study provides new avenues for cascade amplification of the antitumor effects by targeting the tumor microenvironment. This approach may also help avoid unwanted complications.

Gold nanoparticles (AuNPs) have been extensively explored as a drug carrier and have been widely used to provide advanced biomedical research tools in diagnostic imaging and therapy for cancer. Although the mononuclear phagocyte system and immune system are known to play the main roles in the clearance of AuNPs during the circulation, the particle distribution within the immune cells under the condition of immune dysfunction caused by tumor growth has not been thoroughly studied. Here, the cellular distribution of Cy5 labeled AuNPs with diameters of 5, 30 and 50 nm is characterized within the immune populations of the blood, spleen and bone marrow from tumor free and tumor bearing mice using flow cytometry. Tumor-associated immune dysfunction was observed in all immune organs and cell lineages, and it changed with tumor growth. Furthermore, the particle cellular distribution significantly changed in the tumor bearing mice compared with the tumor free mice. Finally, the particle distribution in the immune cells was also different at different stages of the tumor. Overall, these results can help inform and influence future AuNP design criteria including the future applications for nanoparticle-mediated cancer therapy.