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Zijuan Meng,1 Zhaojun Chen,1 Guangwen Lu,1 Xiaoqi Dong,1 Jun Dai,2 Xiaoding Lou,1 Fan Xia1 1Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, People’s Republic of China; 2Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, People’s Republic of ChinaCorrespondence: Jun Dai, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, People’s Republic of China, Email dj_hust1987@sina.com; jundai@tjh.tjmu.edu.cnBackground: White-light photodynamic therapy (wPDT) has been used in the treatment of cancer due to its convenience, effectiveness and less painful. However, the limited penetration of white-light into the tissues leads to a reduced effectiveness of solid tumor treatment.Methods: Two short-wavelength aggregation-induced emission (AIE) nanoparticles were prepared, PyTPA@PEG and TB@PEG, which have excitation wavelengths of 440 nm and 524 nm, respectively. They were characterized by UV, fluorescence, particle size and TEM. The ability of nanoparticles to produce reactive oxygen species (ROS) and kill cancer cells under different conditions was investigated in vitro, including white-light, after white-light penetrating the skin, laser. A white-light fiber for intra-tumor irradiation was customized. Finally, induced tumor elimination with fiber-mediated wPDT was confirmed in vivo.Results: In vitro, both PyTPA@PEG and TB@PEG are more efficient in the production ROS when exposed to white-light compared to laser. However, wPDT also has a fatal flaw in that its level of ROS production after penetrating the skin is reduced to 20– 40% of the original level. To this end, we have customized a white-light fiber for intra-tumor irradiation. In vivo, the fiber-mediated wPDT significantly induces tumor elimination with maximized therapeutic outcomes by irradiating the interior of the tumor. In addition, wPDT also has the advantage that its light source can be adapted to a wide range of photosensitizers (wavelength range 400– 700 nm), whereas a laser of single wavelength can only target a specific photosensitizer.Conclusion: This method of using optical fiber to increase the tissue penetration of white light can greatly improve the therapeutic effect of AIE photosensitizers, which is needed for the treatment of large/deep tumors and holds great promise in cancer treatment.Keywords: aggregation-induced emission, photodynamic therapy, photosensitizer, white light, fiber optic

Object High targeting and efficient cytotoxicity toward tumor cells endow NPs excellent anti-tumor activity. Herein, a peptide polymer possessing dual-targeting ability and double therapeutic activity was developed and named TGMF, which can form NPs through self-assembly. It is composed of four functional modules: 1) Active targeting peptide TMTP1 (T) deliver NPs to tumors specifically; 2) Therapeutic peptide GO-203 (G), which can significantly inhibit tumor growth by disrupting the redox balance in cells; 3) A passively targeted enzyme-responsive peptide PLGLGA (M), which can be cleaved specifically by metalloproteinase-2 (MMP-2) highly expressed in the tumor microenvironment (TME); and 4) Hexadecyl (F), which has strong hydrophobicity, can promote the self-assembly of TGMF NPs. Methods Five modular peptide probes, namely, TGF, TMF, TGM, GMF, and TGMF were synthesized and self-assembled into NPs in solution. The characterization, enzyme reactivity, and cytotoxicity of NPs were evaluated in vitro, and the pharmacokinetics, bio-distribution, anti-tumor activity of NPs were investigated in vivo. In addition, transcriptome sequencing identified the intracellular signaling pathway-related genes involved in the anti-tumor effect of TGMF. Results Upon enzyme cleavage, two types of nanostructure, NPs and nanofibers (NFs), were detected under TEM. Moreover, the cytotoxicity and anti-invasion activity of TGMF against tumor cells used were strongest among the five modular probes examined in vitro. TGMF increased reactive oxygen species (ROS) levels in cytoplasm and produced numerous NFs in extracellular interval and intracellular space. Transcriptome sequencing revealed that TGMF caused 446 genes' down-regulation and 270 genes' up-regulation in HeLa cells. In vivo, TGMF has a good anti-tumor effect, effectively prolonging the survival time of HeLa-tumor-bearing mice without systemic side effects. Conclusion Integration of multiple functional modules into NPs could be a promising strategy for the future of nanomedicine design towards tumor treatment.