Introduction: Induced pluripotent stem cells (iPSCs) have transformed regenerative medicine, enabling patient-specific platforms for disease modeling, drug discovery, and potential cell therapies. Reprogramming somatic cells requires defined transcription factors, notably OCT4, SOX2, KLF4, and c-MYC. However, achieving efficient and safe delivery remains a major obstacle. Conventional viral vectors, while highly effective, pose risks including insertional mutagenesis, immunogenicity, and regulatory hurdles that limit clinical application. Nanoparticle-mediated delivery systems have emerged as a non-integrative alternative, offering controlled spatial and temporal delivery, improved cellular uptake, and combinatorial strategies that emulate physiological factor exposure.
Methods: A systematic literature review was conducted across PubMed, Scopus, and Web of Science for publications between 2020 and 2025. Keywords included “pluripotency induction,” “iPSC reprogramming,” “nanoparticle delivery,” “lipid nanoparticles,” “polymeric nanoparticles,” “magnetic nanoparticles,” “gold nanoparticles,” and “cellular reprogramming efficiency.” Priority was given to high-impact journals such as Cell Stem Cell, Nature Nanotechnology, and Advanced Materials. Selected studies were analyzed to categorize nanoparticles by composition, delivery mechanism, cellular uptake efficiency, cytotoxicity, and their effect on iPSC generation. Data were synthesized to identify comparative advantages, limitations, and strategies to optimize reprogramming outcomes.
Results: Lipid nanoparticles (LNPs) exhibit high efficiency in delivering mRNA or plasmid DNA encoding transcription factors. Their bilayer architecture facilitates endosomal escape and nuclear translocation, enabling rapid and reproducible transfection. While generally well-tolerated, high concentrations can induce cytotoxicity, and efficiency varies among cell types.
Polymeric nanoparticles, including poly(lactic-co-glycolic acid) (PLGA) and polyethyleneimine (PEI)-based systems, enable sustained release of transcription factors, maintaining prolonged cellular exposure that promotes stable pluripotency. Co-delivery with small molecules such as valproic acid or ascorbic acid further enhances cell survival and reprogramming efficiency. Cationic polymers like PEI can induce transient stress, which is mitigated by surface modification without compromising delivery performance.
Magnetic nanoparticles (MNPs) allow spatial and temporal control of factor delivery through external magnetic fields, improving uniform intracellular distribution and minimizing off-target uptake. Limitations include reduced penetration in dense cultures or three-dimensional scaffolds and the need for specialized equipment to achieve precise control.
Gold nanoparticles (AuNPs) offer stable, tunable carriers for transcription factors or growth factors. Optimized size and surface chemistry facilitate receptor-mediated endocytosis, nuclear localization, and long-term intracellular stability. Potential oxidative stress and accumulation necessitate careful particle design and dosing.
Delivery strategies significantly influence reprogramming efficiency. Sequential administration of nanoparticles carrying distinct transcription factors or co-delivery with small molecules outperforms single-dose approaches by replicating the dynamic patterns of transcription factor exposure observed during embryogenesis. Incorporating extracellular matrix cues, such as fibronectin-functionalized nanoparticles, enhances integrin-mediated uptake and cell adhesion. Nanoparticle size, surface charge, and functionalization are critical determinants of internalization: particles under 150 nm predominantly exploit clathrin-mediated endocytosis, whereas larger particles utilize macropinocytosis. Conjugation with targeting ligands, peptides, or antibodies enables selective uptake while minimizing cytotoxicity, providing a highly tunable platform for optimizing pluripotency induction.
Conclusion: Nanoparticle-mediated delivery represents a versatile and safer approach for enhancing iPSC generation. Each class offers distinct advantages: LNPs for rapid transfection, polymeric nanoparticles for sustained release, MNPs for targeted delivery, and AuNPs for controlled stability and uptake. Optimization of composition, dosing, delivery kinetics, and surface functionalization is essential to balance efficiency and cytotoxicity. Future studies should focus on combinatorial and sequential delivery strategies, integration of microenvironmental cues, and scalable manufacturing to advance translational applications in regenerative medicine.
Keywords: Nanoparticle-mediated delivery, Pluripotency induction, iPSC, Regenerative medicine