Table 3.

Representative NP‐based strategies to optimize CAR‐T cell therapy

Non‐viral approaches	Example of NP (or system)	Advantages	Remarks	Ref.
Cationic polymers	PHEMA‐g‐PDMAEMA NPsa)	Successful transfection of T cells with messenger RNA and plasmid DNA with low toxicity (>90% viability)	Optimized the primary T cell transfection conditions	[ 34 ]
Cationic liposomes	Lipid‐based NPs	Mediates in vivo nucleic acid delivery to T cells	T cell proliferation and cytolytic function not compromised	[ 61, 62 ]
Electroporation‐based method	Encapsulation of synthetic mRNA in polymeric PGA NPs	Specific cell subtype targeting, stimulation of receptor‐mediated endocytosis, improved therapeutic potential of programmed T cells	Successful removal of the TRAC region, an important challenge to optimize CAR‐T cell therapy	[ 63 ]
Transposon‐based integration	Polymeric NPs (anti‐CD3‐coupled PEI)	Efficient delivery of DNA cargo into T cells, CAR expression enabled, and in vivo expansion of CAR‐T cells promoted	Technically simpler and generation of potent CAR‐T cells inside the body	[ 35 ]
CRISPR‐CAS9 editing	CRISPR/Cas9‐RNP co‐engineered with nanoparticles	Increased delivery efficiency (up to ≈90%) and great promise for gene repair	Excellent non‐viral editing system reducing off‐target mutations	[ 64, 65 ]
Phenotypic changes	Encoding mRNA for transcriptional factor Foxo13A in NP system	Provided effective immune response	Improved activity of CAR‐T cells in B‐cell lymphoma animal models	[ 66 ]
Epigenetic‐based method	Nanocomplex of miR‐155 mimics and PEI NPs	Reprogramming of tolerogenic DCs into immunostimulatory cells	Potent stimulation of T cell activation	[ 67 ]

^a)Poly(hydroxyethyl methacrylate)‐graft‐poly(2‐(dimethylamino)ethyl methacrylate).