Nanoscale metal-organic frameworks for x-ray activated in situ cancer vaccination

Abstract

Cancer vaccines have been actively pursued to bolster antitumor immunity. Here, we designed nanoscale metal-organic frameworks (nMOFs) as locally activable immunotherapeutics to release danger-associated molecular patterns (DAMPs) and tumor antigens and deliver pathogen-associated molecular patterns (PAMPs) for in situ personalized cancer vaccination. When activated by x-rays, nMOFs effectively generate reactive oxygen species to release DAMPs and tumor antigens while delivering CpG oligodeoxynucleotides as PAMPs to facilitate the maturation of antigen-presenting cells. Together, DAMPs, tumor antigens, and PAMPs expand cytotoxic T cells in tumor-draining lymph nodes to reinvigorate the adaptive immune system for local tumor regression. When treated in combination with an immune checkpoint inhibitor, the local therapeutic effects of nMOF-based vaccines were extended to distant tumors via attenuating T cell exhaustion. Our work demonstrates the potential of nMOFs as x-ray–activable in situ cancer vaccines to awaken the host’s innate and adaptive immune systems for systemic antitumor immunity.

Development of Effective Tumor Vaccine Strategies Based on Immune Response Cascade Reactions

“…[33] Studies have shown that stimulators of interferon gene agonists are also members of the candidate vaccine adjuvant library. [34,35] As the most studied PRR, there have been a variety of TLR agonists as immunostimulatory adjuvants, [36] including the TLR4 agonist monophosphoryl lipid A, [37,38] the TLR9 agonist cytosine phosphodiester guanine (CpG) oligodeoxynucleotide (ODN), [39] and the TLR7/8 agonist imiquimod. [40] The combined use of these adjuvants may produce a synergistic effect.…”

“…By analyzing these physical and chemical properties, nanocarriers that can accurately deliver antigens to LNs and DCs were designed. OVA, Imiquimod, MPL 260 B16-OVA [40] OVA, imidazoquinoline-based esters 156 ± 26 B16-OVA [45] B16-F10 membrane, CpG 120 B16-F10 [82] OVA, HCQ 225.90 ± 2.65 E.G7-OVA [ 108] MPG ΔNLS -OVA 249.5 ± 13.5 E.G7-OVA [ 110] PEG-b-PAGE-b-PLGA OVA 196.5 ± 3.8 Caco-2 [51] PEG-PE, PSA Trp2, CpG 30 B16-F10 [66] PCL-PEI, PCL-PEG Trp2, CpG 80 B16-OVA [86] 3s-PLGA-PO-PEG, PEI OVA 220.4 ± 1.8 ∖ [87] COOH-Pluronic F127/PEOz-PLA OVA, CL264 50 E.G7-OVA [91] PEG-b-PC7A OVA 20-50 B16-OVA [94] DGBA OVA, CpG 105.7-167.7 B16-OVA [95] PLGA, NH 4 HCO 3 OVA 893.63 ± 7.93 B3Z [ 101] pPAA OVA, 𝛼-GalCer 78 B16-OVA [ 106] PLGA @Man-RBC hgp100 25-33 , MPL 149.2 ± 0.6 B16-F10 [ 114] PLH-PEG OVA 124.0 ± 4.780 B16 [ 116] F-PEI OVA 157-250 B16-OVA [ 129] Lipid nanocarrier DP7-C-modified liposome DOTAP, neoantigen mRNA, DP7-C 130.45 ± 9.32 LL2 [41] PLGA-core/lipid-shell hybrid NP mRNA codingOVA, gardiquimod 400 B16-OVA [50] Lipid-PEG NP mRNA coding OVA, G0-C14, C16-R848 137 ± 2.8 E.G7-OVA, RM1-OVA [53] triMN-liposome mRNA coding MART-1 180 TC1, B16, E.G7-OVA [54] Mannose-coated liposome TRP2 180-188 , CpG 102 ± 9 B16-OVA [55] Cationic lipid-assisted NP mRNA coding OVA, MPLA 110 E.G7-OVA [67] Cationic lipid-hybrid NP OVA 236.4 ± 13.2 ∖ [89] Lipid-polymer hybrid NP OVA, MPLA, IMQ 220.77 ± 3.23 EG7-OVA [90] Inorganic nanocarriers nMOF(Hf-DBB F -Ir) CpG 100 MC38, B16-F10, Panc02 [39] GNP OVA 22-33 EG7-OVA [62] XL-MSNs OVA, CpG 100-200 B16-OVA [79] Man-MWCNTs OVA ∖ ∖ [81] MOF(ZIF-8) OVA, CpG 200 ∖ [96] MOF(ZANP) OVA, aluminum, CpG 80 EG7-OVA [97] MS@MOF OVA, PolyIC 100 EG7-OVA [98] CaCO 3 OVA 500 EG7-OVA…”

NIR responsive tumor vaccine in situ for photothermal ablation and chemotherapy to trigger robust antitumor immune responses

“…Personalized TCV in situ represents a promising strategy to overcome tumor heterogeneity by inducing autologous whole tumor antigens release [ 10 – 12 ]. Up to now, a variety of immuno-stimulatory treatments for development of TCV, such as oncolytic viruses [ 13 , 14 ], radiotherapy [ 15 , 16 ], chemotherapy [ 17 ] and phototherapy [ 18 , 19 ], have been reported to generate tumor-associated antigens in situ by inducing immunogenic cell death (ICD) [ 20 – 22 ].…”

Dimethylaminomicheliolide Sensitizes Cancer Cells to Radiotherapy for Synergistic Combination with Immune Checkpoint Blockade

“…There is recent interest in the investigation of small molecule compounds isolated from traditional medicinal plants and heavy metal-based nanoparticles as radiosensitizers. [25][26][27][28] Recent reports have suggested that micheliolide (MCL), a small molecule originally isolated from Michelia compressa and champaca shows anti-inflammatory and anticancer properties. [29][30][31] MCL is a sesquiterpene lactone, a class of natural products containing an 𝛼-methylene-𝛾-lactone moiety and an epoxide group which can interact with proteins to exert a diverse range of biological and pharmacological activities.…”