The persistent high prevalence and poor survival outcomes of lung cancer underscore the urgent need for innovative therapeutic modalities. Here, we present a novel multifunctional delivery platform for the synergistic treatment of lung malignancies, combining in situ-triggerable photodynamic therapy (PDT) with radiotherapy. The new platform CLL was developed by loading a new reactive oxygen species (ROS)-triggerable photosensitizer, luminol-conjugated chlorin e6 (Ce6), into liposomes. CLL can be activated through the bioluminescence resonance energy transfer effect under oxidative stress, thereby producing singlet oxygen for targeted tumor treatment without external irradiation. In vitro studies showed significant cytotoxic effects of CLL in both 4T1 and A549 tumor cells. Furthermore, a PDT-radiopharmaceutical combination nanotherapy CLL-¹⁷⁷Lu was engineered by incorporating the radionuclide ¹⁷⁷Lu into CLL. CLL-¹⁷⁷Lu demonstrated synergistic antitumor effects in 4T1 and A549 tumor cells, as well as in mouse models of 4T1 breast cancer lung metastasis or A549 tumor xenografts. Mechanistically, CLL-¹⁷⁷Lu can induce singlet oxygen/ROS generation, enhance tumor cell apoptosis, and promote M1 macrophage-mediated immunotherapy. Preliminary assessments showed a favorable profile for CLL-¹⁷⁷Lu, highlighting its potential as a promising nanotherapy for cancer treatment. Additionally, CLL can serve as a versatile platform for delivering a range of therapies to achieve synergistic antitumor effects.

Objective To prepare reactive oxygen species(ROS)scavenging Ce6-Luminol encapsulated liposomes(CLL)and to explore the protective effect of CLL against radiation pneumonitis in mice.Methods ROS scavenging material Ce6-Luminol was chemically synthesized,and then was encapsulated using liposome technology to prepare ROS scavenging CLL liposomes.A laser particle size analyzer was used to characterize particle size,polydispersity index,and zeta potential of prepared CLL liposomes.Flow cytometry was employed to detect the uptake of CLL by A549 cells,HUVEC and Raw 264.7 cells,respectively,and CCK-8 assay was utilized to evaluate the cell viability after CLL uptake.The distribution of CLL in the lung tissue of mouse model of radiation lung injury was investigated using In Vivo Imaging System(IVIS).A total of 75 male C57BL/6J mice(6～8 weeks old,17～19 g)were randomly divided into a normal control group(Normal)and CLL treatment groups(0,2,10,and 50 mg/kg),with 15 animal in each group.After the mice in the CLL treatment groups received 15 Gy X-ray irradiation on their chests,they received CLL injection at the corresponding through tail vein on days 0.25,3,and 5 post-irradiation.Then on day 7 post-irradiation,the contents of H2O2,inflammatory cytokines TNF-α and IL-1β,and chemokines monocyte chemoattractant protein(MCP-1)and keratinocyte chemoattractant(KC)in lung tissue,and the proportion of neutrophils in bronchoalveolar lavage fluid(BALF)were measured to evaluate the efficacy of CLL in treatment of radiation pneumonitis in mice.Results The ROS scavenging material Ce6-Luminol was successfully synthesized,and CLL liposomes were prepared,with an average particle size of 127.8±0.5 nm,a polydispersity index of 0.164±0.005,and a Zeta potential of-23.6±1.4 mV.The prepared CLL liposomes were taken up by A549 cells,HUVEC and Raw264.7 cells in a time-and dose-dependent manner,without a sharply decrease in cell viability.IVIS revealed that there were significantly more CLL liposomes distributed in the lung tissues of radiation pneumonitis mice than in normal mice(F=351.741,P＜0.05).CLL intervention significantly reduced the lung contents of H2O2(F=15.183,P＜0.05),TNF-α(F=5.150,P＜0.05),IL-1β(F=10.036,P＜0.05),MCP-1(F=3.777,P＜0.05)and KC(F=3.755,P＜0.05),and the proportion of neutrophils in BALF(F=17.751,P＜0.05)from the radiation pneumonitis mice.Conclusion ROS scavenging CLL liposomes can alleviate radiation pneumonitis in mice,which may be due to the protective role against radiation pneumonitis.