This study developed a novel Janus nanoplatform (J-pHLIP-PD1) by precisely modifying pHLIP peptides and anti-PD-1 antibodies on distinct surfaces, effectively enhancing the engagement between immune cells and tumor cells and restoring intercellular communication, thereby significantly improving anti-tumor immune responses. This platform demonstrated excellent immune activation capabilities both in vitro and in vivo, while avoiding cytokine release syndrome commonly observed in traditional bispecific T cell engager therapies, offering a promising new approach for cancer immunotherapy.
Literature Overview
The paper 'Bi-Functional Topospecific Nanoparticles to Promote Immune-Tumor Cell Engagement as A New Immunotherapeutic Strategy' published in Advanced Materials proposes a novel immune-engager nanosystem that simultaneously targets tumor cells and T cells to promote the formation of immunological synapse-like structures, inducing immunogenic cell death and enhancing anti-tumor immunity. The study validated the therapeutic potential of J-pHLIP-PD1 nanoparticles in both in vitro and in vivo models, showing significant reduction in lung metastases in a metastatic melanoma model, as well as increased infiltration of CD8+ T cells.Background Knowledge
Significant progress has been made in cancer immunotherapy in recent years, with cytotoxic T cells playing a central role in identifying and eliminating tumor cells. However, tumor cells escape immune surveillance through multiple mechanisms, hindering immunological synapse formation and limiting T cell anti-tumor activity. Current bispecific T cell engagers (BiTEs) have achieved some success in hematological malignancies but show limited efficacy in solid tumors, primarily due to their small molecular weight, short half-life, and potential to induce cytokine release syndrome (CRS). Therefore, the development of a new, stable, and spatially oriented nanoplatform that can restore physical contact between immune and tumor cells became the focus of this research. J-pHLIP-PD1 nanoparticles can stably anchor to the tumor cell membrane in acidic microenvironments and recruit T cells through anti-PD-1 antibodies, thereby constructing stable immunological synapses, activating T cells, inducing tumor cell apoptosis, and offering a novel solution for cancer immunotherapy with favorable biocompatibility and tunability.
Research Methods and Experiments
This study designed and synthesized Janus gold-mesoporous silica nanoparticles (J-pHLIP-PD1), with pHLIP peptides covalently attached to the mesoporous silica side for membrane insertion into tumor cells under acidic conditions, and anti-PD-1 antibodies conjugated to the gold side for T cell recruitment. The structure, size, and surface chemical modifications of the nanoparticles were systematically characterized using TEM, STEM-EDX, DLS, and flow cytometry. Subsequently, the effects of the nanoparticles on the binding ability of SK-MEL-103 melanoma cells and Jurkat T cells were evaluated in an in vitro co-culture system, with lactate dehydrogenase (LDH) release, ATP detection, and flow cytometry employed to assess immune cell activation. In vivo, a tail-vein injection model of metastatic B16-F10-Luc melanoma in mice was used to evaluate the nanoparticle’s ability to inhibit lung metastasis and enhance T cell infiltration.Key Conclusions and Perspectives
Research Significance and Prospects
The proposed Janus nanoplatform represents a universal and scalable strategy for cancer immunotherapy by enabling stable immune-tumor cell engagement through spatial orientation. It avoids the engineering complexity and CRS risk associated with traditional BiTE therapy and can be modified with additional therapeutic molecules (e.g., immune checkpoint inhibitors, cytokines, drugs) for combination therapies. Future studies could expand this system to other tumor types and explore its potential in personalized cancer vaccines and T cell engineering.
Conclusion
This study successfully developed a spatially oriented Janus nanoparticle (J-pHLIP-PD1) that can stably anchor in acidic tumor microenvironments and recruit cytotoxic T cells via anti-PD-1 antibodies, restoring physical connections between immune and tumor cells and promoting immunological synapse formation, thereby enhancing anti-tumor immune responses. In vitro, the nanoparticle significantly increased T cell-mediated tumor cell death and induced immunogenic cell death signals. In vivo, the J-pHLIP-PD1 treatment group showed marked suppression of lung metastasis and enhanced T cell infiltration. Compared to traditional bispecific antibody therapies, this system offers superior safety and modular modification potential, providing a new direction for next-generation cancer immunotherapy. With rational design, this platform can be extended to various cancer immunotherapy applications, including combination targeted therapy, vaccine delivery, and gene-edited T cell therapy, offering strong translational potential for clinical development.
