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The efficacy of adoptive T-cell therapy (ACT) against solid tumors is significantly limited by the immunosuppressive tumor microenvironment (TME). Systemic administration of immunostimulants provides insufficient support to ACT cells and often induces systemic toxicity. Here, we propose a cell-surface anchored nucleic acid therapeutic agent (NAT) that robustly enhances ACT by synergistically blocking the immunosuppressive adenosine and PD-1/PD-L1 pathways in tumors. Two different NAT-DNA aptamers target PD-L1 (aptPD-L1) and ATP (aptATP) - designed to form a partially hybridized duplex (aptDual), which can effectively anchor to the cell surface before metastasis. The aptDual, with backpressure, spatially and temporally colocalizes with ACT cells in vivo and infiltrates the ATP-rich TME together. Upon binding to ATP, aptDual dissociates to responsively release aptPD-L1. Simultaneously, aptATP clears extracellular ATP and its metabolite adenosine to disrupt the inhibitory adenosine axis, thereby sensitizing ACT cells to aptPD-L1 immune checkpoint blockade. This dual inhibition results in a significant 40-fold increase in functionally tumor-infiltrating ACT cells, greatly enhancing the efficacy of TCR-T and CAR-T cells in various solid tumor models, even in immunologically "cold" tumors. The NAT backpack provides a simple, multifunctional, and safe strategy to enhance various ACTs against solid tumors.
Innovation 1. The core innovation of this paper lies in proposing a new paradigm for the delivery of nucleic acid therapeutic agents through "cell surface anchoring". Traditional systemic drug administration faces challenges of poor tumor targeting and high toxicity. This study ingeniously attaches therapeutic DNA aptamers directly to the surface of adoptive T cells in the form of hybrid duplexes, essentially equipping each T cell with a "miniature, intelligent drug factory" that can infiltrate the tumor along with it. This design not only achieves precise and efficient enrichment of therapeutic drugs at the tumor site but also ensures a high degree of spatiotemporal coordination between drug action and effector cells, fundamentally overcoming the limitations of traditional methods. 2. Another key innovation is the construction of an intelligent responsive dual immune checkpoint blockade system. The aptDual structure designed in this study is not a simple physical mixture but utilizes high-concentration ATP in the tumor microenvironment as a trigger: when the "backpack" T cells enter the ATP-rich TME, the binding of aptATP to ATP intelligently induces duplex dissociation, thereby releasing aptPD-L1 on demand to block the PD-1/PD-L1 checkpoint. This "environmental trigger-on-demand release" mechanism achieves programmed intervention in the cascade amplification effect of immune suppression signals, that is, first clearing ATP/adenosine through aptATP to relieve global inhibition in the microenvironment, and then releasing aptPD-L1 to remove the "brake" on T cells themselves, producing a powerful synergistic effect. 3. This study demonstrates excellent versatility and safety at the technical level. This NAT backpack strategy does not rely on complex viral vectors or gene editing technology, but can modify multiple types of ACT cells through simple in vitro incubation, showing good universality and simplicity for clinical translation. At the same time, since drug action is limited to the local area infiltrated by T cells, it greatly avoids the toxic side effects that may be caused by systemic immune checkpoint blockade and adenosine pathway inhibition, providing a new technological platform for achieving safer and more effective combined immunotherapy for solid tumors.
Scientific Research Inspiration 1. This study inspires us that when dealing with complex biological regulatory networks, the "modularization" and "systematization" thinking of engineering is crucial. Instead of studying individual targets in isolation, it is better to integrate different functional modules (such as targeting, sensing, and execution) into a synergistic system. The design of aptDual integrates the "sensing module" (sensing ATP) and the "execution module" (blocking PD-L1/clearing adenosine) into one, and this "integrated" treatment strategy provides a clear blueprint for developing the next generation of drugs targeting multifactorial diseases. 2. It emphasizes the treatment strategy of "making the best of the situation and using local resources". The study did not attempt to forcibly alter the entire tumor microenvironment, but instead utilized the inherent characteristics of the TME (such as high ATP) as a trigger signal and employed effector cells (ACT cells) as an ideal drug delivery vehicle. This suggests that future drug design should pay more attention to interacting with physiological or pathological processes in the body, developing "prodrugs" or "smart drugs" that can be specifically activated by the disease microenvironment, thereby maximizing the therapeutic index. 3. This work highlights the great potential of interdisciplinary integration. It closely combines synthetic biology (rational design and programming of nucleic acid aptamers), cell engineering (cell surface anchoring technology), and immunology (deep understanding of immune suppression pathways), creating unprecedented therapeutic tools. This encourages researchers to break down traditional disciplinary barriers and actively draw on concepts and technologies from fields such as materials science, chemistry, and engineering, injecting vitality into solving stubborn challenges in biomedicine.
Thought extension 1. Based on this "cellular backpack" platform, a direct thought extension is to load more diversified immunomodulators. In addition to PD-L1 and adenosine targets, nucleic acid aptamers targeting other checkpoints such as LAG-3, TIM-3, TIGIT, or agonist aptamers capable of activating costimulatory signals, or even cytokine or chemokine mimics that can recruit and activate endogenous immune cells (such as dendritic cells, macrophages) can be considered, thereby constructing a more functionally comprehensive "armed" ACT cell. 2. The intelligent response logic and kinetics of the system can be further optimized. For example, nucleic acid switches that respond to other specific signals in the TME can be designed, or a multi-input logic gating system can be constructed, thus achieving more refined and precise temporal and spatial control of the immunosuppressive loop, further enhancing its specificity and safety. 3. This idea can be extended to other types of cell therapy. For example, can a similar nucleic acid aptamer backpack strategy be applied to tumor-infiltrating lymphocyte, macrophage, or natural killer cell therapy? By equipping these cells with specific "weapons," their application scope in the treatment of cancer, autoimmune diseases, or infectious diseases may be greatly expanded, creating a "universal" cell function enhancement platform.
Similar research ideas 1. Engineering modification of cell surface: Similar research ideas include expressing specific antibody fragments, cytokines, or enzymes capable of degrading immunosuppressive molecules on the surface of AC cells through genetic engineering or chemical methods. The core commonality is "empowering cells" by endowing effector cells themselves or their local microenvironment with new functions to enhance their survival, infiltration, and killing capabilities. 2. Biomaterial-assisted cell delivery: Another similar idea is to utilize degradable hydrogels, nanofiber scaffolds, or microparticles as "artificial microenvironments" to co-load ACT cells and immunomodulatory drugs. These materials can form drug reservoirs in the tumor resection cavity or specific anatomical sites, continuously releasing cytokines or checkpoint inhibitors to support infiltrating T cells. Although the implementation methods differ, the goal is consistent with NAT backpacks - to achieve local and sustained drug delivery. 3. Synthetic biology-driven intelligent cell therapy: This is a deeper similar idea, which involves constructing sensing and response modules within ACT cells through gene circuits. For example, designing gene switches activated by TME signals to induce T cells to express and secrete therapeutic antibodies, cytokines, or enzymes capable of remodeling the microenvironment in situ. Although these research paths differ in technology and complexity, their core philosophy is in line with NAT backpacks - creating "living" therapeutic systems that can autonomously sense the environment and make adaptive responses.
Cell Surface-Tethered Nucleic Acid Therapeutics Program Robust and Tumor-Responsive Enhancement of Adoptive Cell Therapy
Advanced Materials ( IF 26.8 )Pub Date : 2025-05-02DOI: 10.1002/adma.202419969Mengqian Gao, Yingyu Liu, Lei Zhao, Jin Chen, Wenjun Wan, Ze Yuan, Lingyu Li, Yulun Huang, Yajun Wang, Yiran Zheng
