Clay Nanoparticles Elicit Long‐Term Immune Responses by Forming Biodegradable Depots for Sustained Antigen Stimulation

Abstract

Nanomaterials have been widely tested as new generation vaccine adjuvants, but few evoke efficient immunoreactions. Clay nanoparticles, for example, layered double hydroxide (LDH) and hectorite (HEC) nanoparticles, have shown their potent adjuvanticity in generating effective and durable immune responses. However, the mechanism by which clay nanoadjuvants stimulate the immune system is not well understood. Here, it is demonstrated that LDH and HEC-antigen complexes form loose agglomerates in culture medium/serum. They also form nodules with loose structures in tissue after subcutaneous injection, where they act as a depot for up to 35 d. More importantly, clay nanoparticles actively and continuously recruit immune cells into the depot for up to one month, and stimulate stronger immune responses than FDA-approved adjuvants, Alum and QuilA. Sustained antigen release is also observed in clay nanoparticle depots, with 50-60% antigen released after 35 d. In contrast, Alum-antigen complexes show minimal antigen release from the depot. Importantly, LDH and HEC are more effective than QuilA and Alum in promoting memory T-cell proliferation. These findings suggest that both clay nanoadjuvants can serve as active vaccine platforms for sustained and potent immune responses.

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

“…As demonstrated recently, clay nanoadjuvants with antigens loaded form a suitable nodule structure as a loose and soft depot in situ after subcutaneous injection. Compared with commercial adjuvant Alum, such nanocomplexes generate much looser agglomerates within nodules, where antigens are sustainably released and comparable immune cells are actively recruited for continuous immune stimulation over a long period (up to 21 d) …”

2D Layered Double Hydroxide Nanoparticles: Recent Progress toward Preclinical/Clinical Nanomedicine

“…Engineering LDH nanoparticles for immunotherapy has gained increasing interests . Apart from being recognized as a competent vaccine carrier, recent studies have further unveiled the role of LDH itself as an excellent immunotherapeutic adjuvant …”

“…By synthesizing LDH with various compositions, Williams et al concluded that human DCs' response to LDH in vitro is highly correlated with a linear combination of three LDH properties: the radius of M 2+ (or M + ) metal cations, the interlayer spacing, and the surface charge . Chen et al proposed a so‐called depot effect to address the long‐term immune response provoked by LDH . LDHs formed loose aggregates and initiated the long‐term depot effect through slow degradation of LDH.…”

“…Slow degradation would enable the sustained antigen release and moreover, the vacancies in the loose aggregates allow immune cells to enter and take up vaccine released (due to LDH biodegradation) or associated with LDH complexes. Therefore, immune cells (such as DCs) are continuously recruited into the depot and activated and subsequently maintaining the high level of specific immune responses ( Figure ) . Moreover, such a loose aggregate (Depot) disappeared in about 2 months due to the slow biodegradation and cellular uptake, which results in much longer long‐term simulation to the immune response and much weaker inflammation in comparison with the commercial adjuvant Alum .…”

“…These postulated pathways could efficiently induce durable and potent Th1 and Th2 immune responses. Reproduced with permission . Copyright 2018, Wiley‐VCH.…”