Enhanced Cerenkov radiation induced photodynamic therapy based on GSH-responsive biomimetic nanoplatform to trigger immunogenic cell death for tumor immunotherapy

Abstract

Cerenkov radiation (CR) can serve as a source of internal light to overcome the limited tissue penetration of external light in conventional photodynamic therapy (PDT). However, insufficient luminescence intensity hinders the clinical application of CR-PDT. Here, we developed a glutathione-responsive biomimetic nanoplatform by fusing cancer cell membranes and liposomes loaded with photosensitizer hematoporphyrin monomethyl ether (HMME) and a radiation energy amplifier Eu³⁺, named HMME-Eu@LEV. Colloidal Eu³⁺ converts γ-radiation and CR from radioisotopes into fluorescence to enhance anti-tumor effects. Sequential administration ensures co-localization of HMME-Eu@LEV and radiopharmaceutical ¹⁸F-fluorodeoxyglucose (FDG) at the tumor site, triggering enhanced CR-PDT and immunogenic cell death. Our observations indicated that luminescence resonance energy transfer between Eu³⁺ and HMME was efficient, and Cerenkov luminescence from Eu@LEV+FDG was approximately 5.6-fold higher in intensity than that from FDG alone. As a result, abundant ROS were generated, and macrophages in the tumor microenvironment were polarized from M2 to M1. In addition, the immunosuppressive tumor microenvironment could be reversed by promoting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes. The activated immune system effectively inhibited the growth of primary tumors and spread of distant metastases. Our work demonstrates the feasibility of CR-PDT without an external light source and the critical role of nanomaterials in personalized medicine.

Keywords

Cerenkov radiation / Photodynamic therapy / Damage-associated molecular patterns / Immunotherapy / Nanovesicles

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

This work was supported by the Major Science and Technology Special Projects in Henan Province (No. 221100310100) and co-construction Project of Henan Medical Science and Technology (LHGJ20230286). We acknowledge assistance with the access of analytic instruments from Translational Medicine Center at The First Affiliated Hospital of Zhengzhou University. We would like to thank Ms. GuangXin Wang at The Analysis and Testing Center of Institute of Hydrobiology, Chinese Academy of Sciences for discussion and comments on the manuscript.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2025.101070. The figures and tables with "S" before the serial number are included in the Supplementary material.

References

[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63.

[2] Gunaydin G, Gedik ME, Ayan S. Photodynamic therapy for the treatment and diagnosis of cancer-a review of the current clinical status. Front Chem 2021; 9:686303.

[3] Zhao LP, Zheng RR, Kong RJ, Huang CY, Rao XN, Yang N, et al. Self-delivery ternary bioregulators for photodynamic amplified immunotherapy by tumor microenvironment reprogramming. ACS Nano 2022; 16:1182-97.

[4] Zhang C, Wang X, Du J, Gu Z, Zhao Y. Reactive oxygen species-regulating strategies based on nanomaterials for disease treatment. Adv Sci (Weinh) 2021; 8:2002797.

[5] Zhou Z, Song J, Nie L, Chen X. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem Soc Rev 2016; 45:6597-626.

[6] Cao H, Wang L, Yang Y, Li J, Qi Y, Li Y, et al. An assembled nanocomplex for improving both therapeutic efficiency and treatment depth in photodynamic therapy. Angew Chem Int Ed Engl 2018; 57:7759-63.

[7] Wang M, Zhai Y, Ye H, Lv Q Sun B, Luo C, et al. High co-loading capacity and stimuli-responsive release based on cascade reaction of self-destructive polymer for improved chemo-photodynamic therapy. ACS Nano 2019; 13:7010-23.

[8] Ji B, Wei M, Yang B. Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy. Theranostics 2022; 12:434-58.

[9] Goel S, Ferreira CA, Chen F, Ellison PA, Siamof CM, Barnhart TE, et al. Activatable hybrid nanotheranostics for tetramodal imaging and synergistic photothermal/photodynamic therapy. Adv Mater 2018; 30:e1704367.

[10] Kotagiri N, Sudlow GP, Akers WJ, Achilefu S. Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers. Nat Nanotechnol 2015; 10:370-9.

[11] Ai X, Ho CJH, Aw J, Attia ABE, Mu J, Wang Y, et al. In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics. Nat Commun 2016; 7:10432.

[12] Zhang C, Zhao K, Bu W, Ni D, Liu Y, Feng J, et al. Marriage of scintillator and semiconductor for synchronous radiotherapy and deep photodynamic therapy with diminished oxygen dependence. Angew Chem Int Ed Engl 2015; 54:1770-4.

[13] Qian R, Wang K, Guo Y, Li H, Zhu Z, Huang X, et al. Minimizing adverse effects of Cerenkov radiation induced photodynamic therapy with transformable photosensitizer-loaded nanovesicles. J Nanobiotechnol 2022; 20:203.

[14] Ni D, Ferreira CA, Barnhart TE, Quach V, Yu B, Jiang D, et al. Magnetic targeting of nanotheranostics enhances Cerenkov radiation-induced photodynamic therapy. J Am Chem Soc 2018; 140:14971-9.

[15] Cai P, Yang W, He Z, Jia H, Wang H, Zhao W, et al. A chlorin-lipid nanovesicle nucleus drug for amplified therapeutic effects of lung cancer by internal radiotherapy combined with the Cerenkov radiation-induced photodynamic therapy. Biomater Sci 2020; 8:4841-51.

[16] Yu B, Ni D, Rosenkrans ZT, Barnhart TE, Wei H, Ferreira CA, et al. A "missile-detonation" strategy to precisely supply and efficiently amplify Cerenkov radiation energy for cancer theranostics. Adv Mater 2019; 31:e1904894.

[17] Hu Z, Qu Y, Wang K, Zhang X, Zha J, Song T, et al. In vivo nanoparticle-mediated radiopharmaceutical-excited fluorescence molecular imaging. Nat Commun 2015; 6:7560.

[18] Bünzli JC. Lanthanide luminescence for biomedical analyses and imaging. Chem Rev 2010; 110:2729-55.

[19] Zhang Q Pratt EC, Tamura R, Ogirala A, Hsu H-T, Farahmand N, et al. Ultrasmall downconverting nanoparticle for enhanced Cerenkov imaging. Nano Lett 2021; 21:4217-24.

[20] Dong H, Du SR, Zheng XY, Lyu GM, Sun LD, Li LD, et al. anthanide nanoparticles: from design toward bioimaging and therapy. Chem Rev 2015; 115:10725-815.

[21] Pratt EC, Shaffer TM, Zhang Q, Drain CM, Grimm J. Nanoparticles as multimodal photon transducers of ionizing radiation. Nat Nanotechnol 2018; 13:418-26.

[22] Zhen X, Cheng P, Pu K. Recent advances in cell membrane-camouflaged nanoparticles for cancer phototherapy. Small 2019; 15:e1804105.

[23] Dhas N, García MC, Kudarha R, Pandey A, Nikam AN, Gopalan D, et al. Advancements in cell membrane camouflaged nanoparticles: a bioinspired platform for cancer therapy. J Control Release 2022; 346:71-97.

[24] Xu CH, Ye PJ, Zhou YC, He DX, Wei H, Yu CY. Cell membrane-camouflaged nanoparticles as drug carriers for cancer therapy. Acta Biomater 2020; 105:1-14.

[25] Chen Z, Zhao P, Luo Z, Zheng M, Tian H, Gong P, et al. Cancer cell membrane-biomimetic nanoparticles for homologous-targeting dual-modal imaging and photothermal therapy. ACS Nano 2016; 10:10049-57.

[26] Sun H, Su J, Gu W, et al. Meng Q Yin Q Chen L, Cancer-cell-biomimetic nanoparticles for targeted therapy of homotypic tumors. Adv Mater 2016; 28:9581-8.

[27] Qian R, Guo Y, Wang R, Wang S, Gao X, Zhu Z, et al. Cell membrane hybrid lipid nanovesicles enhance innate immunity for synergistic immunotherapy by promoting immunogenic cell death and cGAS activation. Biomater Res 2024; 28:0038.

[28] Wang Z, Li J, Lin G, He Z, Wang Y. Metal complex-based liposomes: applications and prospects in cancer diagnostics and therapeutics. J Control Release 2022; 348:1066-88.

[29] Tang L, Yin Y, Cao Y, Fu C, Liu H, Feng J, et al. Extracellular vesicles-derived hybrid nanoplatforms for amplified CD 47 blockade-based cancer immunotherapy. Adv Mater 2023:e2303835.

[30] Yu X, Sha L, Liu Q, Zhao Y, Fang H, Cao Y, et al. Recent advances in cell membrane camouflage-based biosensing application. Biosens Bioelectron 2021; 194:113623.

[31] Sun L, Liu H, Ye Y, Lei Y, Islam R, Tan S, et al. Smart nanoparticles for cancer therapy. Signal Transduct Target Ther 2023; 8:418.

[32] Qian R, Jing B, Jiang D, Gai Y, Zhu Z, Huang X, et al. Multi-antitumor therapy and synchronous imaging monitoring based on exosome. Eur J Nucl Med Mol Imaging 2022; 49:2668-81.

[33] Gross J, Sayle S, Karow AR, Bakowsky U, Garidel P. Nanoparticle tracking analysis of particle size and concentration detection in suspensions of polymer and protein samples: influence of experimental and data evaluation parameters. EurJ Pharm Biopharm 2016; 104:30-41.

[34] Salou S, Cirtiu CM, Larivière D, Fleury N. Assessment of strategies for the formation of stable suspensions of titanium dioxide nanoparticles in aqueous media suitable for the analysis of biological fluids. Anal Bioanal Chem 2020; 412:1469-81.

[35] Benrabah L, Kemel K, Twarog C, Huang N, Solgadi A, Laugel C, et al. Lipid-based Janus nanoparticles for pharmaceutical and cosmetic applications: kinetics and mechanisms of destabilization with time and temperature. Colloids Surf B Biointerfaces 2020; 195:111242.

[36] Bartczak D, Davies J, Gollwitzer C, Krumrey M, Goenaga-Infante H. Changes in silica nanoparticles upon internalisation by cells: size, aggregation/agglomeration state, mass- and number-based concentrations. Toxicol Res (Camb) 2018; 7:172-81.

[37] Baalousha M, Lead JR. Rationalizing nanomaterial sizes measured by atomic force microscopy, flow field-flow fractionation, and dynamic light scattering: sample preparation, polydispersity, and particle structure. Environ Sci Technol 2012; 46:6134-42.

[38] Gagliardi M, Chiarugi S, De Cesari C, Di Gregorio G, Diodati A, Baroncelli L, et al. Crosslinked chitosan nanoparticles with muco-adhesive potential for intranasal delivery applications. Int J Mol Sci 2023; 24:6590.

[39] Sediq AS, Nejadnik MR, El Bialy I, Witkamp GJ, Jiskoot W. Protein-polyelectrolyte interactions: monitoring particle formation and growth by nanoparticle tracking analysis and flow imaging microscopy. Eur J Pharm Biopharm 2015; 93:339-45.

[40] Thorek DL, Robertson R, Bacchus WA, Hahn J, Rothberg J, Beattie BJ, et al. Cerenkov imaging - a new modality for molecular imaging. Am J Nucl Med Mol Imaging 2012; 2:163-73.

[41] Lee W, Jeon M, Choi J, Oh C, Kim G, Jung S, et al. Europium-diethylenetriaminepentaacetic acid loaded radioluminescence liposome nanoplatform for effective radioisotope-mediated photodynamic therapy. ACS Nano 2020; 14:13004-15.

[42] Ding F, Liu J, Ai K, Xu C, Mao X, Liu Z, et al. Simultaneous activation of pyroptosis and cGAS-STING pathway with epigenetic/photodynamic nanotheranostic for enhanced tumor photoimmunotherapy. Adv Mater 2023;36: e2306419.

[43] Zhou B, Zhang JY, Liu XS, Chen HZ, Ai YL, Cheng K, et al. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res 2018; 28:1171-85.

[44] Zhao M, Zhang Y, Miao J, Zhou H, Jiang Y, Zhang Y, et al. An activatable phototheranostic probe for anti-hypoxic type I photodynamic- and immuno-therapy of cancer. Adv Mater 2023; 36:e2305243.

[45] Irvine DJ, Dane EL. Enhancing cancer immunotherapy with nanomedicine. Nat Rev Immunol 2020; 20:321-34.

[46] Wang C, Shi X, Song H, Zhang C, Wang X, Huang P, et al. Polymer-lipid hybrid nanovesicle-enabled combination of immunogenic chemotherapy and RNAi-mediated PD-L1 knockdown elicits antitumor immunity against melanoma. Biomaterials 2021; 268:120579.

[47] Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12:860-75.

[48] Wan J, Zhang X, Tang D, Liu T, Xiao H. Biodegradable NIR-II pseudo conjugate polymeric nanoparticles amplify photodynamic immunotherapy via alleviation of tumor hypoxia and tumor-associated macrophage reprogramming. Adv Mater 2023; 35:e2209799.

[49] Li D, Liu S, Ma Y, Liu S, Liu Y, Ding J. Biomaterials that induce immunogenic cell death. Small Meth 2023; 7:e2300204.

[50] Yang Z, Luo Y, Yu H, Liang K, Wang M, Wang Q et al. Reshaping the tumor immune microenvironment based on a light-activated nanoplatform for efficient cancer therapy. Adv Mater 2022; 34:e2108908.

[51] Zeng W, Yu M, Chen T, Liu Y, Yi Y, Huang C, et al. Polypyrrole nanoenzymes as tumor microenvironment modulators to reprogram macrophage and potentiate immunotherapy. Adv Sci (Weinh) 2022; 9:e2201703.

[52] Zheng Y, Han Y, Wang T, Liu H, Sun Q, Hu S, et al. Reprogramming tumor-associated macrophages via. Adv Funct Mater 2022; 32:2108971.

[53] Liang J, Zhu F, Cheng K, Ma N, Ma X, Feng Q, et al. Outer membrane vesicle-based nanohybrids target tumor-associated macrophages to enhance trained immunity-related vaccine-generated antitumor activity. Adv Mater 2023; 35:e2306158.

[54] Huang L, Li Y, Du Y, Zhang Y, Wang X, Ding Y, et al. Mild photothermal therapy potentiates anti-PD-L1 treatment for immunologically cold tumors via an all-in-one and all-in-control strategy. Nat Commun 2019; 10:4871.

[55] Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002; 2:251-62.

[56] Guo Y, Lv T, Li Z, Wei X, Yang C, Li W, et al. Acidity-activatable dynamic hybrid nanoplatforms derived from extracellular vesicles of M1 macrophages enhance cancer immunotherapy through synergistic triple immunotherapy. J Nanobiotechnology 2024; 22:430.

[57] Nuccitelli R, McDaniel A, Anand S, Cha J, Mallon Z, Berridge JC, et al. Nano-pulse stimulation is a physical modality that can trigger immunogenic tumor cell death. J Immunother Cancer 2017; 5:32.

[58] Bian Q, Huang L, Xu Y, Wang R, Gu Y, Yuan A, et al. A facile low-dose photosensitizer-incorporated dissolving microneedles-based composite system for eliciting antitumor immunity and the abscopal effect. ACS Nano 2021; 15:19468-79.

[59] Wang L, Guan R, Xie L, Liao X, Xiong K, Rees TW, et al. An ER-targeting iridium(III) complex that induces immunogenic cell death in non-small-cell lung cancer. Angew Chem Int Ed Engl 2021; 60:4657-65.

[60] Li Z, Lai X, Fu S, Ren L, Cai H, Zhang H, et al. Immunogenic cell death activates the tumor immune microenvironment to boost the immunotherapy efficiency. Adv Sci (Weinh) 2022; 9:e2201734.

[61] Xiu Z, Sun T, Yang Y, He Y, Yang S, Xue X, et al. Curcumin enhanced ionizing radiation-induced immunogenic cell death in glioma cells through endoplasmic reticulum stress signaling pathways. Oxid Med Cell Longev 2022; 2022:5424411.

[62] Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011; 334:1573-7.

[63] Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother Cancer 2018; 6:57.

[64] Duan X, Zou H, YangJ, Liu S, Xu T, DingJ. Melittin-incorporated nanomedicines for enhanced cancer immunotherapy. J Control Release 2024; 375:285-99.

[65] Fotooh Abadi L, Kumar P, Paknikar K, Gajbhiye V, Kulkarni S. Tenofovir-tethered gold nanoparticles as a novel multifunctional long-acting anti-HIV therapy to overcome deficient drug delivery-: an in vivo proof of concept. J Nanobiotechnol 2023; 21:19.

[66] Liu N, Su X, Sun X. Cerenkov radiation-activated probes for deep cancer theranostics: a review. Theranostics 2022; 12:7404-19.

[67] Chen R, Yang J, Wu M, Zhao D, Yuan Z, Zeng L, et al. M2 macrophage hybrid membrane-camouflaged targeted biomimetic nanosomes to reprogram inflammatory microenvironment for enhanced enzyme-thermo-immunotherapy. Adv Mater 2023; 35:e2304123.