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

Conspectus Layered double hydroxide (LDH)is an anionic two-dimensional plate-likenanomaterial consisting of positively charged divalent and trivalentcation layers and anion-exchangeable interlayer galleries alternatingly.In the past decades, LDH has been widely explored as a versatile drugdelivery system (DDS) for delivering small molecules, genes, peptides,and proteins due to its excellent drug-loading capacity and feasiblesurface modification. At the cellular level, LDH can be easily internalizedby cells, escape rapidly (<30 min) from endosomes/lysosomes, andsubsequently diffuse into the cytoplasm and mitochondria, which provides an important basis for achieving subcellular organelle-targeted drugdelivery. At the body level, LDH is able to actively target differentorgans by optimizing the physicochemical properties (e.g., size andcolloidal stability) and surface modification. Beyond DDS, LDH hasbeen used as an antacid drug Talcid for nearly half a century, andits chemical composition is also highly similar to commercial aluminumadjuvants; thus, LDH has been redefined as a new type of antacid nanoaluminumadjuvant for cancer immunotherapy. Notably, the flexible compositionof LDH enables its metal cations and defect sites in the LDH layerto be tailored according to the needs of cancer immunotherapy. Onthe one hand, doping nutritional metal cations into LDH layers cangreatly enhance the ability of LDH to activate immune cells and inducetumor immunogenic cell death, thereby improving its efficiency ininducing systemic immune responses. On the other hand, the modulationof defect sites in the crystal structure of LDH enables itself tosensitively respond to external stimuli for photothermal/photodynamictherapy, sonodynamic therapy, and pH-sensitive magnetic resonanceimaging. Therefore, two-dimensional LDH nanomaterials with high physicochemicalplasticity are emerging as drug-free or drug-minimal candidates forvisualized cancer immunotherapy. In this Account, we brieflyintroduce the application of LDH asDDS in delivering small molecules, genes, peptides, proteins, andvaccines against malignant tumors, as well as the related surfacemodification strategies for enhancing LDH-based nanomedicine/vaccineaccumulation in the targeted tissues. Then, we highlight our group'swork in preparing drug-free or drug-minimal LDH for efficient cancerimmunotherapy beyond DDS. We are focusing on exploring the influenceof the intrinsic physicochemical properties of LDH on its activationof the immune system, induction of tumor cell death, and evocationof protective antitumor immune responses. The perspectives associatedwith the application of immunomodulatory LDH for visualized cancerimmunotherapy are also discussed. We envision that these drug-freeor drug-minimal LDH nanomaterials for cancer immunotherapy will stimulatethe development of simple and highly effective immunomodulatory nanomaterialsto fight cancer.