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iNature
Delivering therapeutic proteins directly to intracellular targets remains a huge challenge
.
On November 18, 2022, Sun Agile of China Pharmaceutical University and Gu Zhen of Zhejiang University jointly published an online report entitled "Pore forming–mediated intracellular protein delivery for enhanced cancer immunotherapy" online in Science Advances (IF=15).
The study used CD8+ T cells to open holes in cell membranes to develop a method of
intracellular protein delivery.
This study uses CD8+ T cells to form pores in the plasma membrane of tumor cells, perfuse ribonuclease A (RNase A) and granzyme B into the cells, thereby effectively inducing apoptosis and pyroptosis by activating the caspase 3 and gasdermin E pathways, and enhancing CD8+ T cell-mediated immunotherapy
.
RNase A, programmed cell death ligand 1 antibodies, and photothermal agents are then loaded into injectable hydrogels for the treatment of low immunogenic mouse breast cancer
.
Notably, three courses of laser irradiation induced effective apoptosis and immune activation, and the treatment effect was remarkable, with 75% of tumors removed without recurrence
.
.
Commercial protein therapies primarily target the extracellular space
.
So far, several strategies such as forming lipid or polymer delivery systems or applying electroporation techniques have been developed to address these issues
.
Although the assembly of protein drugs with vectors can lead to protein denaturation, the specific devices required for electroporation techniques are limited
in vivo applications.
Therefore, there is an urgent need to develop better clinical translation methods to achieve efficient intracellular protein delivery
.
CD8+ T cells or natural killer (NK) cells secrete perforin (PRF) to exert their cytotoxicity
.
PRF can be inserted into the cell membrane, forming multiple transmembrane pores
on the target cell.
The size of these pores is generally greater than 10 nm, while the commonly applied protein drugs are between 1-10 nm, so proteins can enter the intracellular space
directly through the pores.
CD8+ T cells are the primary mediator of the anti-tumor immune response, and many methods have been developed to introduce CD8+ T cells into tumors, including vaccines, photothermal therapy (PTT), photodynamic therapy, chemotherapy, or radiotherapy
.
Among them, PTT can trigger a strong anti-tumor immune response
by inducing immunogenic cell death (ICD) of tumor cells, making "cold" tumors "hot", promoting the initiation and infiltration of CD8+ T cells in tumor tissues.
Mechanism pattern diagram (Figure from Science Advances) In this study, CD8+ T cell-induced plasma membrane pores were used to promote intracellular transmission of proteins to achieve synergistic anti-tumor effects
。 In this design, the hydrophobic photosensitizer IR780 was coated with human serum albumin (HSA@IR780, HIR780), ribonuclease A (RNase A), and poloxamer 407 (P407)/α-cyclodextrin (α-CD), which were gelled
in situ by intratumoral injection.
A mild photothermal effect of 45 °C under laser irradiation can induce ICD and activate the immune response while minimizing denaturation of coated protein therapy and tissue damage
to normal tissues.
High temperatures can trigger the decomposition of hydrogels and accelerate the release
of RNase A.
The activated CD8+ T cells then secrete PRF to form pores in the tumor cell membrane, perfuse RNase A into the cell, degrade the intracellular RNA, and then activate the caspase 3 (Cas 3) pathway to kill the tumor cells
.
The pores formed by CD8+ T cell-mediated intracellular protein delivery can guide the clinical use of cancer immunotherapy and accelerate the clinical transformation
of targeted protein drugs into intracellular targets.
Original link: —END—the content is [iNature].
