Domestic Cell Therapy Breakthrough: 'Nanoantibody Armor' Technology Doubles Survival in Solid Tumor Patients

Recently, Shanghai Cell Therapy Group announced that its globally pioneering "nano-antibody armored" CAR-T cell therapy (NAC-T) has achieved significant efficacy in patients with relapsed or refractory malignant mesothelioma – the median overall survival reached 25.6 months, more than doubling the existing second-line treatment options. The related findings were recently published in the prestigious international journals *Advanced Science* and *Nucleic Acids Research*, marking a critical leap in China's solid tumor CAR-T therapy field from "catching up" to "leading."

For a long time, CAR-T cell therapy has shown excellent performance in hematological tumors but has repeatedly encountered setbacks in the treatment of solid tumors, mainly limited by two major bottlenecks: First, after CAR-T cells enter the tumor microenvironment, they quickly become "exhausted," losing their killing ability; second, traditional viral vectors have safety concerns and are expensive, restricting the widespread application of the therapy. To address these two global challenges, Shanghai Cell Therapy Group has achieved independent innovation, simultaneously overcoming the dual barriers of "efficacy" and "safety."

On one hand, the research team innovatively equipped CAR-T cells with a layer of "smart nano-armor" – utilizing self-developed llama-derived anti-PD-1 nanobodies, which are only one-tenth the size of traditional antibodies and possess stronger tumor tissue penetration. More crucially, the team designed a "chimeric promoter" system, enabling the nanobody to be activated and secreted locally with high efficiency only after the CAR-T cells recognize and bind to the tumor antigen. This "on-demand release" mechanism increases drug concentration in the tumor microenvironment by over 6500 times, effectively blocking the PD-1 immune suppression pathway and reversing T-cell exhaustion. In the first-in-human Phase I clinical trial, 11 patients with malignant mesothelioma who had failed standard treatments received NAC-T cell infusions. Results showed an overall objective response rate (ORR) of 63.6%. Particularly encouraging was that one patient with complete remission has remained tumor-free for up to 45.6 months.

While enhancing therapeutic efficacy, the team simultaneously addressed another major pain point of CAR-T therapy — the safety and accessibility of the gene delivery system. Traditional CAR-T therapies rely on viral vectors for gene editing, which are not only costly and complex in terms of manufacturing processes, but also carry potential risks such as insertional mutagenesis. To address this, the Shanghai Cell Therapy Group collaborated with Yangzhou University, Shanghai University, and other institutions to conduct an in-depth engineering transformation of the BZ transposon system derived from zebrafish, successfully developing a highly efficient and safe novel non-viral vector — the Baize (BZ) transposon system. By employing strategies such as combinatorial mutagenesis, dimer fusion, and structural prediction, the team constructed several "hyperactive" transposase mutants. Among these, the core variant BZ325 demonstrated activity 2.3 times higher than that of the wild type at low doses. Additionally, the team developed a "mini-plasmid" of just 800bp, which significantly improved the integration efficiency and expression levels of the CAR gene while ensuring functionality.

"Armored Nanobodies" Break Through the Efficacy Bottleneck, "Non-Viral Vectors" Cross the Safety Threshold

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