Table 2 Characteristics of mRNA cancer vaccine delivery methods

In vivo injection of naked mRNA

Direct injection of mRNA into the patient

Expression of the antigen by host cells

Simple and low cost

Low transfection efficiency and immunogenicity

Inflammation at the injection site

Preclinical and early clinical trials

Melanoma, prostate cancer, infectious diseases

[61]

Lipid nanoparticles (LNPs)

mRNA encapsulated in a lipid nanoparticle for delivery

Facilitate cellular uptake and mRNA release

High transfection efficiency and immunogenicity

Potential toxicity and accumulation in liver

Immune response to the lipid components

Clinical trials ongoing

Various cancer types, infectious diseases

[128]

Electroporation

Electrical pulse applied to cells to increase permeability

Enhance mRNA delivery and uptake

High transfection efficiency and immunogenicity

Pain and muscle contractions

Electrode burn and tissue damage

Early clinical trials

Melanoma, breast cancer, head and neck cancer

[129]

Dendritic cell loading

mRNA loaded into dendritic cells (DCs) for antigen presentation

Increase antigen presentation and T cell activation

Efficient and targeted delivery

Complex and costly production process

DC maturation and activation

Preclinical and early clinical trials

Various cancer types

[130]

Polymeric nanoparticles

mRNA encapsulated in a polymeric nanoparticle for delivery

Facilitate cellular uptake and mRNA release

Biodegradable and biocompatible

Lower transfection efficiency than LNPs

Potential toxicity and accumulation in liver

Preclinical trials

Various cancer types, infectious diseases

[131]

Protamine-condensed mRNA

mRNA condensed with protamine for delivery

Facilitate cellular uptake and mRNA release

Efficient and low cost

High toxicity and immunogenicity

Non-specific activation of immune cells

Preclinical trials

Various cancer types, infectious diseases

[132]

mRNA-coated gold nanoparticles

mRNA adsorbed onto gold nanoparticles for delivery

Facilitate cellular uptake and mRNA release

Efficient and targeted delivery

Potential toxicity and accumulation in liver

Gold nanoparticles may activate immune cells

Preclinical trials

Various cancer types, infectious diseases

[133]

In vitro transcribed mRNA-loaded exosomes

mRNA loaded into exosomes for delivery

Facilitate cellular uptake and mRNA release

Targeted delivery and high stability

Lower transfection efficiency than LNPs

Immunogenicity of the exosomes

Preclinical trials

Various cancer types

[66]

Synthetic polymeric vectors

mRNA encapsulated in a synthetic polymeric vector for delivery

Facilitate cellular uptake and mRNA release

Biocompatible and biodegradable

Lower transfection efficiency than LNPs

Potential toxicity and accumulation in liver

Preclinical trials

Various cancer types

[134]

Self-amplifying mRNA vaccines

mRNA encoding self-replicating RNA for delivery

Amplification of mRNA expression in vivo

High immunogenicity and long-term antigen expression

Potential toxicity and long-term safety concerns

Immune response to the viral components

Early clinical trials

Various cancer types

[2]

mRNA-carrying oncolytic viruses

mRNA loaded into oncolytic viruses for delivery

Selective replication in cancer cells and antigen presentation

Tumor-specific delivery and amplification of mRNA expression

Potential toxicity and systemic spread

Immune response to the viral components

Preclinical trials

Various cancer types

[135]

mRNA-nanocomplexes

mRNA encapsulated in a nanoparticle for delivery

Facilitate cellular uptake and mRNA release

Efficient and targeted delivery

Potential toxicity and accumulation in liver

Immune response to the delivery vehicle

Preclinical trials

Various cancer types

[136]

mRNA-loaded hydrogels

mRNA embedded in a hydrogel matrix for delivery

Facilitate cellular uptake and mRNA release

Sustained release and targeted delivery

Lower transfection efficiency than LNPs

Inflammation and fibrosis at the injection site

Preclinical trials

Various cancer types

[2]

mRNA-loaded microneedles

mRNA coated on microneedles for dermal delivery

Facilitate cellular uptake and mRNA release

Simple and painless administration

Limited to dermal applications

Risk of skin irritation and infection

Preclinical trials

Various cancer types, infectious diseases

[137]

mRNA-electrospun fibers

mRNA encapsulated in electrospun fibers for delivery

Facilitate cellular uptake and mRNA release

Sustained release and targeted delivery

Limited to topical applications

Biocompatibility and toxicity concerns

Preclinical trials

Various cancer types, infectious diseases

[138]

mRNA delivery via ultrasound-targeted microbubble destruction

mRNA delivered to the site of interest using ultrasound and microbubbles

Increased cellular uptake and gene expression at the site of interest

Targeted delivery, non-invasive

Limited to superficial tumors, small area of effect

Safety of microbubbles

Preclinical trials

Various cancer types

[139]

mRNA delivery via magnetofection

mRNA complexed with magnetic particles and delivered using a magnetic field

Enhanced cellular uptake and transfection

Targeted delivery, non-invasive

Limited to superficial tumors, small area of effect

Safety of magnetic particles

Preclinical trials

Various cancer types

[140]

mRNA delivery via nanoparticles with tumor-penetrating peptides

mRNA encapsulated in nanoparticles functionalized with tumor-penetrating peptides

Facilitates the penetration of mRNA-containing nanoparticles into tumor tissue

Enhanced tumor-targeting, high transfection efficiency

Limited to solid tumors

Safety of nanoparticles

Preclinical trials

Solid tumors

[141]

mRNA delivery via bacterial vectors

mRNA loaded into attenuated bacteria and delivered to tumor site

Amplifies antigen presentation and tumor-specific immune response

Enhanced immunogenicity, targeted delivery

Potential for bacterial infection and immune response

Safety of bacterial vectors

Preclinical trials

Various cancer types

[142]

mRNA delivery via hyaluronan nanogels

mRNA encapsulated in hyaluronan-based nanogels and delivered to the site of interest

Increased cellular uptake and transfection at the site of interest

Targeted delivery, non-toxic

Limited to superficial tumors, small area of effect

Safety of nanogels

Preclinical trials

Various cancer types

[143]

mRNA delivery via bioresponsive polymeric nanoparticles

mRNA encapsulated in polymeric nanoparticles designed to degrade in response to specific stimuli

Facilitates site-specific mRNA delivery

Targeted delivery, non-toxic

Limited to tumors that can be targeted by specific stimuli

Safety of nanoparticles

Preclinical trials

Various cancer types

[144]

mRNA delivery via tissue engineering scaffolds

mRNA incorporated into tissue engineering scaffolds and delivered to the site of interest

Enhanced cellular uptake and transfection at the site of interest

Site-specific delivery, potentially long-term antigen expression

Limited to solid tumors and tissue-engineered sites

Safety of scaffolds

Preclinical trials

Various cancer types, tissue engineering

[145]

mRNA delivery via extracellular vesicles

mRNA encapsulated in extracellular vesicles derived from a patient's own cells and delivered to the site of interest

Enhanced tumor-targeting, high transfection efficiency

Targeted delivery, non-toxic

Limited to solid tumors

Safety of extracellular vesicles

Preclinical trials

Solid tumors

[146]

mRNA delivery via in vivo electroporation

mRNA delivered to tissue via electroporation

Facilitates cellular uptake and gene expression

Targeted delivery, non-toxic

Limited to specific tissue types and requires specialized equipment

Risk of tissue damage from electroporation

Preclinical trials, some clinical trials

Various cancer types

[147]

mRNA delivery via dissolvable microneedle arrays

mRNA coated onto dissolvable microneedles and applied to skin

Facilitates cellular uptake and gene expression in skin

Targeted delivery, non-invasive

Limited to skin and superficial tumors

Safety of microneedles

Preclinical trials

Skin cancers

[148]

mRNA delivery via laser ablation

mRNA delivered to tissue via laser ablation

Facilitates cellular uptake and gene expression

Targeted delivery, non-toxic

Limited to specific tissue types and requires specialized equipment

Risk of tissue damage from laser ablation

Preclinical trials

Various cancer types

[149]

mRNA delivery via microfluidic chips

mRNA delivered to cells via microfluidic chips

Facilitates cellular uptake and gene expression

Targeted delivery, precise control over flow rates and concentrations

Limited to specific cell types and requires specialized equipment

Safety of microfluidic chips

Preclinical trials

Various cancer types

[150]

mRNA delivery via electrospray

mRNA delivered to tissue via electrospray

Facilitates cellular uptake and gene expression

Targeted delivery, non-toxic

Limited to specific tissue types and requires specialized equipment

Safety of electrospray

Preclinical trials

Various cancer types

[151]

mRNA delivery via cell-penetrating peptides

mRNA complexed with cell-penetrating peptides and delivered to cells

Facilitates cellular uptake and gene expression

Targeted delivery, non-toxic

Limited to specific cell types

Safety of cell-penetrating peptides

Preclinical trials

Various cancer types

[152]

mRNA delivery via gene gun

mRNA coated onto gold particles and delivered to tissue via gene gun

Facilitates cellular uptake and gene expression

Targeted delivery, non-toxic

Limited to specific tissue types and requires specialized equipment

Risk of tissue damage from gene gun

Preclinical trials

Various cancer types

[153]

mRNA delivery via polymeric carriers

mRNA complexed with biodegradable polymeric carriers and delivered to tissue

Facilitates cellular uptake and gene expression

Targeted delivery, non-toxic, controlled release

Limited to specific tissue types and requires specialized equipment

Safety of polymeric carriers

Preclinical trials

Various cancer types

[154]

mRNA delivery via lipoplexes

mRNA complexed with lipids and delivered to cells

Facilitates cellular uptake and gene expression

Non-toxic, efficient

Limited to specific cell types

Safety of lipids

Preclinical trials

Various cancer types

[155]

mRNA delivery via dendrimers

mRNA complexed with dendrimers and delivered to cells

Facilitates cellular uptake and gene expression

Non-toxic, efficient

Limited to specific cell types

Safety of dendrimers

Preclinical trials

Various cancer types

[156]

mRNA delivery via gold nanoparticles

mRNA complexed with gold nanoparticles and delivered to cells

Facilitates cellular uptake and gene expression

Non-toxic, efficient

Limited to specific cell types

Safety of gold nanoparticles

Preclinical trials

Various cancer types

[133]

mRNA delivery via viral vectors

mRNA loaded into viral vectors and delivered to cells

Facilitates cellular uptake and gene expression

High transfection efficiency, targeted delivery

Risk of immune response and viral integration

Safety of viral vectors

Preclinical trials

Various cancer types

[157]

mRNA delivery via cell-based vehicles

mRNA loaded into various cell types and delivered to target tissues

Facilitates cellular uptake and gene expression

Non-toxic, potential for targeting and controlled release

Limited to specific cell types and requires specialized equipment

Safety of cell-based vehicles

Preclinical trials

Various cancer types

[158]

mRNA delivery via exosomes

mRNA encapsulated in exosomes and delivered to target tissues

Facilitates cellular uptake and gene expression

Non-toxic, potential for targeting and controlled release

Limited to specific tissues

Safety of exosomes

Preclinical trials

Various cancer types

[159]

mRNA delivery via ribonucleoprotein complexes

mRNA complexed with ribonucleoproteins and delivered to cells

Facilitates cellular uptake and gene expression

Non-toxic, efficient

Limited to specific cell types

Safety of ribonucleoproteins

Preclinical trials

Various cancer types

[147]

mRNA delivery via inorganic nanoparticles

mRNA complexed with inorganic nanoparticles and delivered to cells

Facilitates cellular uptake and gene expression

Non-toxic, efficient, targeted delivery

Limited to specific cell types

Safety of inorganic nanoparticles

Preclinical trials

Various cancer types

[147]

mRNA delivery via sonoporation

mRNA delivered to tissue via ultrasound-mediated sonoporation

Facilitates cellular uptake and gene expression

Non-invasive, targeted delivery

Limited to specific tissue types and requires specialized equipment

Risk of tissue damage from sonoporation

Preclinical trials

Various cancer types

[160]

mRNA delivery via gas-filled microbubbles

mRNA delivered to tissue via microbubble-assisted ultrasound

Facilitates cellular uptake and gene expression

Non-invasive, targeted delivery

Limited to specific tissue types and requires specialized equipment

Safety of microbubbles

Preclinical trials

Various cancer types

[161]

mRNA delivery via electrical fields

mRNA delivered to cells via electrical fields

Facilitates cellular uptake and gene expression

Non-toxic, efficient

Limited to specific cell types and requires specialized equipment

Safety of electrical fields

Preclinical trials

Various cancer types

[162]

mRNA delivery via bacterial vectors

mRNA loaded into bacterial vectors and delivered to cells

Facilitates cellular uptake and gene expression

Targeted delivery, high transfection efficiency

Risk of immune response and bacterial infection

Safety of bacterial vectors

Preclinical trials

Various cancer types

[147]

mRNA delivery via CRISPR-Cas systems

mRNA encoding CRISPR-Cas system delivered to cells

Facilitates targeted gene editing

Precise, efficient

Limited to specific cell types and requires specialized equipment

Safety of CRISPR-Cas system

Preclinical trials

Various cancer types

[163]

mRNA delivery via cell-penetrating antibodies

mRNA complexed with cell-penetrating antibodies and delivered to cells

Facilitates cellular uptake and gene expression

Non-toxic, potential for targeting and controlled release

Limited to specific cell types

Safety of cell-penetrating antibodies

Preclinical trials

Various cancer types

[164]

mRNA delivery via non-viral vectors

mRNA complexed with non-viral vectors and delivered to cells

Facilitates cellular uptake and gene expression

Non-toxic, efficient, potential for targeted delivery

Limited to specific cell types

Safety of non-viral vectors

Preclinical trials

Various cancer types

[165]