Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell-surface markers

Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(2), С. 102520 - 102520

Опубликована: Март 20, 2025

Efficient delivery of mRNA-lipid nanoparticles (LNPs) to specific cell types remains a major challenge for mRNA therapeutics. Conventional targeting approaches involve modifying the lipid composition or functionalizing surface LNPs, which complicates manufacturing and alters nanoparticle size, charge, stealth, impacting their immunogenicity. Here, we present generalizable method targeted mRNA-LNP that uses bispecific antibodies (BsAbs) form bridge between LNPs markers. BsAbs can be combined with administered first, binding proteins on target cells later retaining unmodified in affected tissues. We demonstrate efficient cell-type-specific mRNA-LNPs beyond liver, epidermal growth factor receptor (EGFR)- folate hydrolase 1 (PSMA)-positive vitro vivo. The flexibility this technology, achieved by substituting cell-targeting region BsAbs, enables rapid development next-generation drugs.

Язык: Английский

The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances

Biomedicines, Год журнала: 2025, Номер 13(4), С. 857 - 857

Опубликована: Апрель 2, 2025

Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of activation inhibition cancer, influence microenvironment, latest advancements cell-based immunotherapies, including adoptive transfer Chimeric Antigen Receptor-Natural Killer (CAR-NK) therapies. Methods: A comprehensive literature was conducted, prioritizing peer-reviewed studies from last decade on biology, evasion, immunotherapeutic applications. The analysis includes data preclinical models clinical trials evaluating expansion strategies, cytokine-based stimulation, CAR-NK therapy developments. Results: eliminate through granule release, death receptor pathways, cytokine secretion. evade NK-mediated immunity downregulating activating ligands, secreting immunosuppressive molecules, altering microenvironment. Novel therapies, such as combination approaches with checkpoint inhibitors, enhance persistence therapeutic efficacy against both hematologic solid malignancies. Clinical suggest improved safety profiles compared CAR-T reduced release syndrome graft-versus-host disease. Conclusions: While immunotherapies hold great promise, challenges remain, limited tumor-induced immunosuppression. Addressing these hurdles will be critical for optimizing therapies advancing next-generation, off-the-shelf immunotherapeutics broader

Язык: Английский