Beyond Drug Delivery System: Immunomodulatory Layered Double Hydroxide Nanoadjuvants Take an Essential Step Forward in Cancer Immunotherapy

Layered double hydroxide (LDH) is an anionic two-dimensional plate-like nanomaterial consisting of positively charged divalent and trivalent cation layers and anion-exchangeable interlayer galleries alternatingly. In the past decades, LDH has been widely explored as a versatile drug delivery system (DDS) for delivering small molecules, genes, peptides, and proteins due to its excellent drug-loading capacity and feasible surface modification. At the cellular level, LDH can be easily internalized by cells, escape rapidly (<30 min) from endosomes/lysosomes, and subsequently diffuse into the cytoplasm and mitochondria, which provides an important basis for achieving subcellular organelle-targeted drug delivery. At the body level, LDH is able to actively target different organs by optimizing the physicochemical properties (e.g., size and colloidal stability) and surface modification. Beyond DDS, LDH has been used as an antacid drug Talcid for nearly half a century, and its chemical composition is also highly similar to commercial aluminum adjuvants; thus, LDH has been redefined as a new type of antacid nanoaluminum adjuvant for cancer immunotherapy. Notably, the flexible composition of LDH enables its metal cations and defect sites in the LDH layer to be tailored according to the needs of cancer immunotherapy. On the one hand, doping nutritional metal cations into LDH layers can greatly enhance the ability of LDH to activate immune cells and induce tumor immunogenic cell death, thereby improving its efficiency in inducing systemic immune responses. On the other hand, the modulation of defect sites in the crystal structure of LDH enables itself to sensitively respond to external stimuli for photothermal/photodynamic therapy, sonodynamic therapy, and pH-sensitive magnetic resonance imaging. Therefore, two-dimensional LDH nanomaterials with high physicochemical plasticity are emerging as drug-free or drug-minimal candidates for visualized cancer immunotherapy. In this Account, we briefly introduce the application of LDH as DDS in delivering small molecules, genes, peptides, proteins, and vaccines against malignant tumors, as well as the related surface modification strategies for enhancing LDH-based nanomedicine/vaccine accumulation in the targeted tissues. Then, we highlight our group’s work in preparing drug-free or drug-minimal LDH for efficient cancer immunotherapy beyond DDS. We are focusing on exploring the influence of the intrinsic physicochemical properties of LDH on its activation of the immune system, induction of tumor cell death, and evocation of protective antitumor immune responses. The perspectives associated with the application of immunomodulatory LDH for visualized cancer immunotherapy are also discussed. We envision that these drug-free or drug-minimal LDH nanomaterials for cancer immunotherapy will stimulate the development of simple and highly effective immunomodulatory nanomaterials to fight cancer.