Layered double hydroxide (LDH) is a ‘sandwich’-like two-dimensional clay material that has been systematically investigated for biomedical application in the past two decades. LDH is an alum-similar adjuvant, which has a well-defined layered crystal structure and exhibits high adjuvanticity. The unique structure of LDH includes positively charged layers composed of divalent and trivalent cations and anion-exchangeable interlayer galleries. Among the many variants of LDH, MgAl-LDH (the cationic ions are Mg²⁺ and Al³⁺) has the highest affinity to antigens, bioadjuvants and drug molecules, and exhibits superior biosafety. Past research studies indicate that MgAl-LDH can simultaneously load antigens, bioadjuvants and molecular drugs to amplify the strength of immune responses, and induce broad-spectrum immune responses. Moreover, the size and dispersity of MgAl-LDH in biological environments can be well controlled to actively deliver antigens to the immune system, realizing the rapid induction and maintenance of durable immune responses. Furthermore, the functionalization of MgAl-LDH nanoadjuvants enables it to capture antigens in situ and induce personalized immune responses, thereby more effectively overcoming complex diseases. In this review, we comprehensively summarize the development and application of MgAl-LDH nanoparticles as a vaccine adjuvant, demonstrating that MgAl-LDH is the most potential adjuvant for clinical application.

With the in-depth exploration on cancer therapeutic nanovaccines, increasing evidence shows that the poor delivery of nanovaccines to lymphoid organs has become the culprit limiting the rapid induction of anti-tumor immune response. Unlike the conventional prophylactic vaccines that mainly form a depot at the injection site to gradually trigger durable immune response, the rapid proliferation of tumors requires an efficient delivery of nanovaccines to lymphoid organs for rapid induction of anti-tumor immunity. Optimization of the physicochemical properties of nanovaccine (e.g., size, shape, charge, colloidal stability and surface ligands) is an effective strategy to enhance their accumulation in lymphoid organs, and nanovaccines with dynamic structures are also designed for precise targeted delivery of lymphoid organs or their subregions. The recent progress of these nanovaccine delivery strategies is highlighted in this review, and the challenges and future direction are also discussed. Graphical Abstract