The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.201908185.Cell-membrane-derived biomimetic nanoplatforms have revolutionized the design of cancer vaccine by providing targeted delivery, specific recognition, antigen presentation, and immune stimulation [1] and diverse eukaryotic membrane vesicles have been developed for vaccine design, including blood cells, [2] Adv.

Herein we report that dimensional reduction from three-dimensional nanoscale metal–organic frameworks (nMOFs) to two-dimensional nanoscale metal–organic layers (nMOLs) increases the frequency of encounters between photosensitizers and oxygen and facilitates the diffusion of singlet oxygen from the nMOL to significantly enhance photodynamic therapy. The nMOFs and nMOLs share the same M12–oxo (M = Zr, Hf) secondary building units and 5,15-di-p-benzoatoporphyrin (DBP) ligands but exhibit three-dimensional and two-dimensional topologies, respectively. Molecular dynamics simulations and experimental studies revealed that the nMOLs with a monolayer morphology enhanced the generation of reactive oxygen species and exhibited over an order of magnitude higher cytotoxicity over the nMOFs. In a mouse model of triple-negative breast cancer, Hf-DBP nMOL showed 49.1% more tumor inhibition, an 80% higher cure rate, and 16.3-fold lower metastasis potential than Hf-DBP nMOF.

Despite potent preclinical antitumor activity, activation of stimulator of interferon genes (STING) has shown modest therapeutic effects in clinical studies. Many STING agonists, including 2′,3′‐cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), show poor pharmacokinetic properties for sustaining STING activation in tumors and achieving optimal antitumor efficacy. Improved delivery of STING agonists and their effective combination with other treatments are needed to enhance their therapeutic effects. Herein, a 2D nanoplatform, cGAMP/MOL, is reported via conjugating cGAMP to a nanoscale metal–organic layer (MOL) for simultaneous STING activation and radiosensitization. The MOL not only exhibits strong radiosensitization effects for enhanced cancer killing and induction of immunogenic cell death, but also retains cGAMP in tumors for sustained STING activation. Compared to free cGAMP, cGAMP/MOL elicits stronger STING activation and regresses local tumors upon X‐ray irradiation. Further combination with an immune checkpoint inhibitor bridges innate and adaptive immune systems by activating the tumor microenvironment to elicit systemic antitumor responses.

Ineffective antigen cross-presentation in the tumor microenvironment compromises the generation of antitumor immune responses. Radiotherapy–radiodynamic therapy (RT-RDT) with nanoscale metal–organic frameworks (nMOFs) induces robust adaptive immune responses despite modest activation of canonical antigen presenting dendritic cells. Here, using transplantable and autochthonous murine tumor models, we demonstrate that RT-RDT induces antitumor immune responses via early neutrophil infiltration and reprogramming. Intravenous or intratumoral injection of nMOFs recruited peripheral CD11b+Ly6G+CD11c– neutrophils into tumors. The activation of nMOFs by low-dose X-rays significantly increased the population of CD11b+Ly6G+CD11c+ hybrid neutrophils with upregulated expression of the co-stimulatory molecules CD80 and CD86 as well as major histocompatibility complex class II molecules. Thus, nMOF-enabled RT-RDT reshapes a favorable tumor microenvironment for antitumor immune responses by reprogramming tumor-infiltrating neutrophils to function as non-canonical antigen presenting cells for effective cross-presentation of tumor antigens.

photon-matter interactions, the photoelectric process is more likely to occur on high-Z elements where photoelectrons are ejected following photon absorption. Auger electrons are further generated after the holes are filled by higher-orbital electrons. In addition, inorganic nanoparticles (NPs) usually possess higher densities compared to organic molecules, leading to further enhancement of energy deposition on a per unit space basis. As a result, various studies have explored the potential of high-Z element-based nanoradiosensitizers such as gold nanoparticles (Au NPs) and hafnium oxide nanoparticles (HfO 2 NPs) to amplify the generation of photoelectrons and Auger electrons. Hainfeld et al. reported improved survival of EMT-6 mammary carcinoma-bearing mice by 1 year after treatment with Au NPs and X-rays. [32] Notably, NBTXR3, a 50 nm HfO 2 NP developed by Nanobiotix, received European market approval (CE Mark) as a medical device for the treatment of locally advanced soft tissue sarcoma in 2019. [33,34] The sizes of NPs can impact their radiosensitizing effects. [35] In the study of Au NPs with various sizes, Misawa et al. found that smaller Au NPs showed greater yields of ROS including hydroxyl radical and superoxide, [36] suggesting the positive effects of high surface areas on NP radiosensitization. However, the interplay between a nanoradiosensitizer and a biological system is much more complicated. First, NPs of sizes ranging from 10 to 200 nm can preferentially accumulate in tumor tissues via the enhanced permeability and retention effect. [37] NPs smaller than 10 nm can be easily cleared through renal filtration without significant accumulation in tumors. [38] Second, the sizes of NPs also affect their cellular uptake. [39] Chithrani et al. studied size-dependent Au NPs uptake in mammalian cells and found that 50 nm Au NPs showed higher cellular uptake when compared to 14 and 70 nm Au NPs. [40] Similarly, NBTXR3 was engineered with a size of 50 nm to enhance cancer cell uptake. [41] We recently reported the design of nanoscale metal-organic frameworks (nMOFs) comprising metal-oxo cluster secondary building units (SBUs) and organic bridging ligands and examined their potential use as a novel class of nanoradiosensitizers. [42][43][44][45] We hypothesized that highly porous nMOFs might afford unprecedentedly high radiosensitization with an Nanoscale metal-organic frameworks (nMOFs) have recently been shown to provide better radiosensitization than solid nanoparticles (NPs) when excited with X-rays. Here, a Monte Carlo simulation of different radiosensitization effects by NPs and nMOFs using a lattice model consisting of 3D arrays of nanoscale secondary building units (SBUs) is reported. The simulation results reveal that lattices outperform solid NPs regardless of radiation sources or particle sizes via enhanced scatterings of photons and electrons within the lattices. Optimum dose enhancement can be achieved by tuning SBU size and inter-SBU distance.