Zhejiang University Lists for Transfer a Novel Tannic Acid-Iron-Modified Dual-Photosensitizer Loaded Upconversion Nanoparticle Platform for Synergistic Chemo-Photodynamic and Immuno-Oncology Therapy

Recently, Zhejiang University“Iron Tannate-Modified Dual Photosensitizer-Loaded Upconversion Nanoparticles: Preparation Method and Applications”Announcement on the Public Disclosure of Achievement Transformation, Proposed to350,000 yuan plus sales commissionin a manner that transfers the technology to industry partners.

This patent is byCen Dong, Cai Xiujun, Deng Renren, Li Xiangcompleted jointly, among whichAcademician Cai XiujunWith extensive expertise in hepatobiliary and pancreatic surgery and oncology diagnosis and treatment, he has received prestigious awards such as the Liang Heli Science and Technology Innovation Award and the Major Contribution Award of the Zhejiang Provincial Science and Technology Award. He pioneered techniques such as laparoscopic suction-scraping anatomical hepatectomy and established China’s first discipline of minimally invasive medicine.Researcher Cen DongCurrently an attending physician in the Department of General Surgery at this hospital, he focuses on interdisciplinary research in minimally invasive medicine, specializing in the development and clinical translation of smart implantable devices (such as hydrogels and medical fibers).

This patent falls within the field of bionanomaterials, specifically relating to the preparation and performance evaluation of a nanotherapeutic platform that leverages the synergistic effects of chemodynamic therapy and photodynamic therapy while inducing immunogenic cell death in tumors, thereby enhancing antitumor immune responses.

Its technological core lies inComposite Nanoparticles with a Diameter of 100 nm, this particle is based on upconversion nanoparticles with a four-layer core-shell structure, loaded with dual photosensitizers Ce6 and MC540, and adsorbed with iron-tannic acid complexes. To address the challenges of limited photodynamic efficacy and insufficient immune response in traditional tumor therapy, this technology utilizes 808 nm near-infrared light excitation to achieve"Chemodynamic-Photodynamic"Synergistic antitumor effects, induction of immunogenic cell death in tumors, and combination with immune checkpoint inhibitors to enhance therapeutic efficacy.

Furthermore, this platform integrates tumor CT and MRI imaging capabilities, successfully establishing a “theranostic” nanotherapeutic platform that opens new avenues for the precise treatment of malignant tumors.

Malignant TumorMalignant tumors are major diseases that pose a serious threat to human health. Currently, the primary treatments for malignant tumors include surgical resection, chemotherapy, radiotherapy, and immunotherapy. However, these methods have certain limitations: advanced-stage tumors are often unresectable; chemotherapy is associated with systemic toxicity and a high propensity for drug resistance; the hypoxic tumor microenvironment limits the efficacy of radiotherapy; and immunotherapy is characterized by suboptimal response rates and high costs. Therefore, there is an urgent clinical need to explore innovative cancer treatment strategies.

The development and progression of tumors are closely associated with the uncontrolled proliferation of tumor cells and their evasion of immune surveillance.. Tumor cells possess the ability to proliferate indefinitely due to their migratory capacity and loss of contact inhibition. Meanwhile, tumor cells evade surveillance and elimination by the host immune system through various mechanisms. Specifically, an ideal tumor treatment strategy should not only effectively kill tumor cells but also activate the body’s anti-tumor immune response, thereby achieving comprehensive cancer therapy.

With the continuous advancement of nanotechnology, its applications in biomedical fields such as tumor diagnosis and treatment have become increasingly widespread, paving the way for various tumor therapeutic strategies, including photothermal therapy, photodynamic therapy, and chemodynamic therapy.Photodynamic Therapy(Photodynamic Therapy, PDT) refers to the use of laser light at specific wavelengths to irradiate photosensitizers, which then transfer energy to oxygen molecules, thereby generating reactive oxygen species (ROS) to kill tumor cells.

Photosensitizers used in conventional photodynamic therapy (PDT) require excitation by ultraviolet-visible light to function; however, the limited tissue penetration depth of ultraviolet-visible light significantly restricts its application in the treatment of solid or deep-seated tumors. In contrast, near-infrared (NIR) light falls within the “optical window” of biological tissues, enabling effective penetration. By leveraging upconversion nanoparticles (UCNPs), NIR light can be converted into visible or ultraviolet light to activate photosensitizers, thereby achieving photodynamic therapy. Through rational design of UCNP structures and optimization of energy transfer efficiency, the therapeutic efficacy of upconversion-based PDT can be significantly enhanced.Chemodynamic Therapy(Chemodynamic therapy, CDT) is an emerging tumor treatment strategy that utilizes Fenton reagents to react with H₂O₂ at the tumor site, generating hydroxyl radicals that effectively kill tumor cells.

PDT and CDT Therapeutic SystemsAll possess the potential to induce immunogenic cell death (ICD) in tumor cells. Existing studies have demonstrated that photodynamic therapy (PDT) can effectively induce ICD in tumor cells; however, its induction efficiency is limited within the hypoxic tumor microenvironment. Furthermore, chemodynamic therapy (CDT) can also induce ICD when combined with other modalities such as chemotherapy.

Therefore, constructing a synergistic CDT/PDT therapeutic system can not only enhance the efficiency of PDT-induced immunogenic cell death (ICD) by ameliorating the tumor hypoxic microenvironment but also potentially exert a synergistic effect in inducing ICD through the combined action of CDT and PDT.

Currently, clinical modalities for tumor imaging include fluorescence imaging, computed tomography (CT), and magnetic resonance imaging (MRI). Theranostic platforms that integrate these tumor imaging capabilities offer significant advantages in the precise treatment of tumors. Therefore, the development of nanoparticles that combine these functionalities is of considerable significance.

To address the aforementioned issues, the team developedTechnology of Upconversion Nanoparticles Modified with Iron Tannate and Dual Photosensitizers.This technology achieves synergistic chemodynamic-photodynamic therapy and induces immunogenic cell death by constructing four-layer core-shell upconversion nanoparticles loaded with dual photosensitizers and adsorbed with iron-tannic acid complexes, while also possessing CT/MRI multimodal imaging capabilities.has formed a "diagnosis and treatment integration" solution, to overcome the limitations of existing technologies.

From the perspective of functional synergy, this technology pioneers an integrated system combining “chemodynamic therapy–photodynamic therapy–immunotherapy + multimodal imaging”:On one hand, the absorption peaks of the dual photosensitizers Ce6 and MC540 fully overlap with the emission peaks of the four-layer core–shell upconversion nanoparticles, enabling highly efficient enhancement of photodynamic therapy (PDT) under 808 nm near-infrared light excitation. Meanwhile, the iron–tannic acid complex (FeTA) responds to the acidic tumor microenvironment, not only triggering chemodynamic therapy (CDT) via Fenton reactions but also generating oxygen to alleviate tumor hypoxia, thereby further sensitizing PDT. This achieves highly synergistic CDT and PDT, overcoming the limited efficacy of conventional monotherapies. On the other hand, this system can effectively induce immunogenic cell death (ICD) in tumors. When combined with immune checkpoint inhibitors, it significantly enhances anti-tumor immune responses and breaks through immune evasion barriers. Additionally, it possesses dual-modal imaging capabilities for computed tomography (CT) and magnetic resonance imaging (MRI), allowing precise tumor localization and therapeutic efficacy assessment, thus providing real-time guidance for adjusting diagnosis and treatment strategies.

In terms of technological breakthroughs, the design of upconversion nanoparticles with a four-layer core-shell structure demonstrates significant innovation:Using NaGdF₄ as the host matrix, precise control over the doping ratios of rare-earth elements such as Yb, Tm, Nd, and Er (e.g., a 49:1 Yb:Tm doping ratio in the NaGdF₄:Yb,Tm layer and a 10:10 Nd:Yb ratio in the NaGdF₄:Nd,Yb layer) enables efficient absorption and energy conversion of 808 nm near-infrared light. This approach addresses the bottleneck of traditional photosensitizers, which rely on ultraviolet-visible light excitation and suffer from insufficient tissue penetration depth. Furthermore, surface coating with SiO₂ and amino functionalization of the nanoparticles not only enhance biocompatibility but also provide a stable carrier for dual-photosensitizer loading and iron-tannic acid complex adsorption, ensuring effective integration of various functional modules. The preparation process is simple and cost-controllable, demonstrating strong potential for large-scale production.

In terms of clinical adaptability, this technology closely aligns with clinical needs:The composite nanoparticles, with a diameter of approximately 100 nanometers, exhibit excellent biocompatibility and targeting capabilities, enabling precise accumulation at tumor sites. In vitro cellular and in vivo animal studies have demonstrated that this system has low toxicity to normal cells while effectively inhibiting tumor growth. Furthermore, when combined with immunotherapy, it can suppress distant tumors, making it suitable for the treatment of multifocal or metastatic cancers. This approach provides a new therapeutic option for patients with advanced-stage disease and significantly enhances its potential for clinical translation.

From the perspective of academic research progress and industrial product layout,Photodynamic therapy (PDT) exploration in the oncology field has formed diverse tracks, including technological breakthroughs addressing the pain points of traditional PDT and clinical implementation of mature products. This can be specifically outlined from the following dimensions:

In academia, innovative research addressing the core challenges of PDT continues to emerge.

1. A synergistic treatment regimen centered on "improvement of the hypoxic microenvironment."For example, the Combo-NP nanoparticles, jointly developed by the University of South China, Xiangya Hospital, and Peking University, achieve tumor vascular normalization by loading the angiogenesis inhibitor lenvatinib. This approach alleviates hypoxia while inducing immunogenic cell death (ICD), and when combined with PD-L1 inhibitors, it significantly inhibits the metastasis of uveal melanoma. Additionally, the IM@iPPAE@siMCT4 nanosystem, developed by Chen Jun’s team at the Chinese Academy of Sciences and Hu Yi’s team at the Chinese Academy of Medical Sciences, integrates a photosensitizer (ICG), nanozymes (iron oxide particles), and a lactate transporter inhibitor (siMCT4). This system not only directly kills tumor cells through photodynamic therapy (PDT) but also blocks lactate efflux to reverse tumor metabolic symbiosis, while enhancing chemodynamic therapy (CDT) efficacy in acidic environments, thereby forming a triple synergistic effect of “PDT + CDT + metabolic regulation.”

Second, breakthroughs in novel photosensitizers and targeted delivery technologies.The "Report on the Development of Oncology Disciplines in China (2024)" highlights the optimization of plant-derived photosensitizers, such as enhancing targeting specificity by conjugating chlorophyll derivatives with water-soluble proteins and inducing ferroptosis via hypericin. Advances have also been made in intelligent delivery systems, including mitochondria-targeted PSs@BSAs nanoparticles and pH/GSH dual-responsive photosensitizer platforms.

Furthermore, innovations in light source technology have expanded the application scenarios of PDT.The wireless, battery-free esophageal stent developed by Xue Xinyu’s team at the University of Electronic Science and Technology of China integrates an ultrasound-driven light source with an electrochemical pneumatic actuator, enabling autonomous movement within a 200 mm range and precise targeting to improve the efficacy of esophageal cancer treatment. The red-and-blue dual-wavelength flexible LED patch developed by Lu Min’s team at Shanghai Jiao Tong University combines synergistic therapy using red light (630 nm) and blue light (470 nm) to promote chronic wound healing and provide antibacterial treatment. These technologies effectively address the limitations of traditional light sources, such as shallow penetration and poor adaptability.

In the industry, several PDT drugs have achieved clinical translation and are focused on different tumor indications.

Chinese enterprises are leading in their strategic layout in this field.Fudan-ZhangjiangThe second-generation photosensitizer “AiLa” (aminolevulinic acid hydrochloride), developed in-house, was approved in 2007 for the treatment of condyloma acuminatum. Among its indication-expansion projects, those targeting cervical intraepithelial neoplasia and moderate-to-severe acne have completed Phase II clinical trials; the project for actinic keratosis has entered Phase II clinical trials; and the projects for intraoperative visualization guidance in glioma and bladder cancer have both advanced to pivotal clinical stages. The overseas registration project for Hemoporfin (Fumeida®) is currently undergoing Phase II clinical trials in the United States.

In addition, Fudan-Zhangjiang is also developing novel near-infrared photosensitizers intended for the treatment of deep-seated refractory diseases affecting the skin and serosal membranes.

Chongqing Maile Bio's "Xibofen"(Hematoporphyrin Injection) was approved as a Class 1 new drug by the China National Medical Products Administration in 2006. It targets and destroys tumor cells through photodynamic reactions and is indicated for the treatment of superficial cancers and precancerous lesions in the oral cavity, bladder, lungs, and other sites.

Hisun Pharmaceutical, Longhua Pharmaceutical, and other companiesSeveral photosensitizers under development are also advancing into clinical stages, with a primary focus on the treatment of solid tumors.

Internationally,Soligenix, Inc.SGX301 (synthetic hypericin topical ointment) has demonstrated sustained efficacy in Phase 3 clinical trials for cutaneous T-cell lymphoma and is classified as a “first-in-class” photodynamic therapy; porfimer sodium, an earlier-approved agent, remains widely used in the treatment of deep-seated tumors such as esophageal and lung cancers, serving as a commonly employed PDT drug in clinical practice.

Overall,Current research and products in the field of photodynamic therapy (PDT) revolve around “enhancing efficacy, expanding indications, and optimizing safety.” Academia focuses on technological innovation and breakthroughs (such as combination therapies and targeted delivery), while industry concentrates on the clinical translation and iteration of mature technologies. The “tannic acid-iron modified dual-photosensitizer nanoparticles” transferred by Zhejiang University this time have formed a differentiated advantage in the existing track with their integrated design of “PDT + CDT + immune synergy + multimodal imaging,” especially in solving the problem of hypoxia and the synergy of immune activation, filling the functional gap of current PDT technology.