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Review
. 2024 Jun 28;22(1):380.
doi: 10.1186/s12951-024-02630-1.

Steering the course of CAR T cell therapy with lipid nanoparticles

Muhammad Babar Khawar #  1   2   3 , Ali Afzal #  4   5 , Yue Si  1   2 , Haibo Sun  6   7
Affiliations
Review

Steering the course of CAR T cell therapy with lipid nanoparticles

Muhammad Babar Khawar et al. J Nanobiotechnology. .

Abstract

Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and addressing challenges like immunogenicity, reduced toxicity, and improved safety. Promising preclinical results signal a shift toward safer and more effective CAR T cell treatments. Ongoing research aims to validate these findings in clinical trials, marking a new era guided by LNPs utility in CAR therapy. Herein, we explore the preference for LNPs over traditional methods, highlighting the versatility of LNPs and their effective delivery of nucleic acids. Additionally, we address key challenges in clinical considerations, heralding a new era in CAR T cell therapy.

Keywords: Chimeric antigen receptor; Immunotherapy; Lipid nanoparticles; Nonviral transduction; mRNA delivery.

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Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Basic designs of chimeric antigen receptor (CAR) and lipid nanoparticle (LNPs) for CAR delivery. A 1st gen CARs rely on immunoreceptor tyrosine-based activation motifs for TCR-associated signaling. 2nd gen CARs enhance proliferation and cytotoxicity by adding CD28 or CD137 co-stimulatory domains. CD28 activates phosphoinositide 3-kinases (PI3K) for improved cytokine production and cell survival; CD137 activates nuclear factor kappa B (NF-κB) pathway. 3rd gen CARs combine CD137 or CD134, activating NF-κB and MAPK for enhanced survival and memory T cell formation. 4th gen CARs secrete desired cytokines, promoting tumor killing via exocytosis or death ligand–death receptor systems. 5th gen CARs, based on 2nd gen, incorporate IL2 receptor β-chain with STAT3 binding, providing antigen-specific activation, T cell receptors (TCR), co-stimulation, and cytokine signals for full T cell activation and proliferation. B Positively charged cationic lipids bind and condense mRNA, neutral lipids provide stability, and PEGylation enhances circulation. mRNA, encapsulated in LNPs, protects and delivers the therapeutic cargo. Helper lipids and cholesterol enhance stability, while stabilizers and buffering agents optimize performance. Optionally, targeting ligands improve specificity, promoting binding, uptake, and internalization for enhanced therapeutic precision and reduced off-target effects. Examples include antibodies or peptides which guide engineered T cells to selectively target thereby eliminating cancer cells
Fig. 2
Fig. 2
The interplay between capsid size, onco-mutations, and immunogenicity. The constraints stem from the 100 nm diameter of capsids in adenoviruses and lentiviruses, posing challenges for gene cassettes over 8–9 kb. Insertional mutagenesis introduces the risk of oncogenic insertions during construct integration. Viral vectors carry inherent immunogenicity, infecting various antigen-presenting cells (APCs) like DCs, macrophages, or B cells. This prompts APCs to express viral antigens, initiating events culminating in T cell activation and adaptive immune responses. Moreover, viral gene expression induces cytokine production, attracting immune cells and fostering an immune-activating microenvironment
Fig. 3
Fig. 3
Safety and Efficiency of LNPs in delivering CAR-mRNA constructs. Viral proteins may induce inflammatory responses within host cells, affecting the cellular environment and impacting CAR mRNA delivery success. LNPs, with PEGylation, exhibit lower immunogenicity compared to viral vectors. The mRNA in CAR constructs is protected by a lipid layer, shielding it from endonucleases, cytokines, and insertional mutagenesis. LNPs offer a versatile platform with customizable formulations, allowing tailored lipid composition for specific gene delivery needs. LNPs maintain stability in biological fluids, ensuring genetic payload integrity and improving overall delivery efficiency. Certain LNPs can be engineered for cell-specific targeting, enhancing precision in gene delivery. LNPs scalability and reproducibility support potential translation from research to clinical applications
Fig. 4
Fig. 4
LNPs mediated delivery of nucleic acids. A The process begins with formulating LNPs, comprised of lipids, cholesterol, and PEGylated lipids. These self-assemble to encapsulate nucleic acids through electrostatic, hydrogen, and hydrophobic interactions. Stabilizing agents like PEG enhance LNP stability. Intracellular uptake involves endocytosis, facilitated by cell surface receptors. Endosomal escape and cytoplasmic release are crucial for delivering nucleic acids, allowing translation and biological activity. Metabolism and clearance handle unused components. B LNPs traditionally target hepatocytes for mRNA delivery. Recent advancements enable LNPs to effectively deliver mRNA to non-hepatocytes, broadening therapeutic targeting beyond liver cells. Progress in ApoE- and LDL receptor-independent pathways enhances the versatility of LNPs in targeting diverse cell types. C Structure of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and D 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
Fig. 5
Fig. 5
Efficiency of LNPs with PEGylation. Following IV administration, brush-like PEGylation show increased plasma protein adsorption when compared to club-shaped PEGylation or mushroom-like. Also, PEGylation influence LNPs size, its surface charge, and the capability of gene silencing. Next to extravasation, lightly PEGylated LNPs have shown enhanced activation and expansion of tumor resident antigen presenting cells when compared to largely PEGylated has shown reduced effects
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