Metal ions play critical roles in many immune processes, and their modulation may open up new forms of vaccine adjuvants. Current vaccines predominantly utilize aluminum salts as adjuvants, but alum has poor ability to induce cellular immunity. Manganese (Mn²⁺) can activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway for amplifying cellular immune responses, but free Mn²⁺ may cause certain neurotoxicity due to its random in vivo distribution. Herein, Mn²⁺ is initially biomineralized into human serum albumin nanoparticles (HSA-Mn) to improve the biocompatibility of Mn adjuvants. Then, HSA-Mn and alum adjuvants are co-dispersed at the squalene/water interphase, resulting in a bimetallic adjuvant co-stabilized Pickering nanoemulsion (HMANE). Compared to lecithin-stabilized emulsion, HMANE increased the surface roughness by approximately 6-fold and significantly improved its interactions with antigen-presenting cells (APCs). After vaccination, HMANE-adjuvanted inactivated SARS-CoV-2 virus (CorV-HMANE) rapidly induced antibody generation and efficiently activated the STING pathway to produce a stronger cellular immune response. In addition, the abundant memory B and T cells induced by the CorV-HMANE further ensured its long-term protective efficacy for at least 4 months. In conclusion, our study highlights the great potential of Pickering emulsions as metal adjuvant platforms, providing new insight for further adjuvant development.

Being a Th2 stimulator, classic aluminum salt-based adjuvants only stimulate weak cellular immune responses that are required for vaccination against intracellular viruses or cancerous cells. As a third-generation bisphosphonate, zoledronate (ZOL) can enhance antigen cross-presentation by inhibiting key enzymes of the mevalonate pathway. Here, we developed the subunit antigen ovalbumin (OVA) and ZOL co-loaded aluminum hydroxide nanoparticles (APN-OVA-ZOL) and investigated their capacity for inducing cellular immune responses against the antigen. Our results showed that the developed nanovaccines could successfully encapsulate OVA and ZOL, and enabled efficient lymph node delivery. Benefited by the mevalonate pathway inhibition effect of ZOL, APN-OVA-ZOL significantly promoted cross-presentation. As a result, APN-OVA-ZOL induced robust cellular immunity, including the activation of T and B cells. In a EG7-OVA tumor-bearing murine model, APN-OVA-ZOL significantly inhibited the tumor growth and prolonged mice survival. This work provided a strong empirical foundation indicating that zoledronate-loaded aluminum salt nanovaccines had a strong potency for cancer immunotherapy.

Current therapeutic limitations existed in effective treatment of rheumatoid arthritis (RA) have motivated numerous researches on finding new strategies. Regarding to the non-targeted distribution and uncontrollable in vivo performance which hinder the effective treatment for RA, we designed an acid-responsive polymeric micelle formulation by attaching the dexamethasone (Dex) to the side chains of a wheat-like polyethylene glycol (PEG) derivate via a hydrazone linker. The self-assembly micelles with the diameter around 50 nm could passively migrate to inflamed sites. The presence of hydrazone linkers avoided the drug leakage in circulation and ensured the preferential release in acidic arthritic joints. Here, we evaluated how the polymer-drug micelles with different density of drug payloads influenced the release pattern, pharmacokinetics and biodistribution, as well as the most importantly, the duration of the therapeutic efficacy. Our exploration would offer the chemical and structural basis for designing and optimizing the nanocarriers for enhanced therapeutic efficacy.

In recent years, messenger RNA (mRNA) vaccines have been intensively studied in the fields of cancer immunotherapy and infectious diseases because of their excellent efficacy and safety profile. Despite significant progress in the rational design of mRNA vaccines and elucidation of their mechanism of action, their widespread application is limited by the development of safe and effective delivery systems that protect them from ubiquitous ribonucleases (RNases), facilitate their entry into cells and subsequent escape from endosomes, and target them to lymphoid organs or particular cells. Some mRNA vaccines based on lipid carriers have entered clinical trials. Vaccines based on polymers, while not as clinically advanced as lipid vectors, show considerable potentials. In this review, we discuss the necessity of formulating mRNA vaccines with delivery systems, and we provide an overview of reported delivery systems.