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Cytotoxic T lymphocytes (CTLs) are the key effector cells in anti-tumor immunity, and their killing function mainly relies on granzyme B (GrB) triggering a caspase cascade reaction in the cytoplasm of target cells, thereby inducing programmed cell death. Natural GrB, as a protein drug, faces multiple challenges in clinical translation, including limited in vitro stability, high production costs, and the lack of an efficient cytoplasmic delivery strategy. In contrast, although CAR-T therapy has achieved success in hematological malignancies, it is still constrained by factors such as low tumor infiltration efficiency, immunosuppressive microenvironment, and the risk of systemic toxic side effects in the solid tumor environment. Therefore, how to reproduce the key apoptotic triggering环节in the cytoplasm of tumor cells without relying on live cell therapy becomes a research direction of engineering significance.
To this end， Professor Huang Xingluo from Nankai University， Professor Liu Yijin from Nankai University， and Professor Stephen Mann from the University of Bristol in the UK collaborated to propose a "bottom-up" molecular engineering strategy. The researchers used human heavy-chain ferroferredoxin nanocages as protein scaffolds and through site-specific binding of Pd(II) ions， constructed a metal catalytic center composed of bimetallic palladium ions within the protein subunits， thereby obtaining a protein nanoenzyme (FTn-Pd) with GrB substrate selectivity. This artificial catalytic center does not replicate the mechanism of natural serine proteases but acquires new hydrolytic functions through local conformational rearrangement induced by metal coordination. The researchers further encapsulated FTn-Pd in biomimetic lipid nanovesicles (GMNVs) displaying anti-HER2 single-chain antibodies (ScFv) on the surface， and utilized the membrane fusion mechanism driven by cationic lipids to enable the nanoenzyme to bypass the classical endocytosis-lysosome pathway and directly enter the cytoplasm of tumor cells， thereby functioning within the cell without relying on perforin. The innovation of this design lies in the delivery strategy of cytoplasmic GrB-like active nanoenzymes， rather than the reconstruction of the complete killing process of immune cells.
Original link：
https://www.nature.com/articles/s41467-026-68773-x?sessionid=
