Advanced Control of Silica Nanoparticle Size for Optimized Drug Delivery Systems

Abstract Silica nanoparticles (SiNPs) have gained significant attention in nanomedicine due to their tunable size, stability, and biocompatibility. Among the many factors influencing their performance in drug delivery, particle size is one of the most critical, as it affects biodistribution, cellular uptake, and therapeutic efficiency. This article reviews the key synthesis parameters that govern nanoparticle size, including precursor concentration, catalyst type, solvent composition, temperature, and reaction time.

It also highlights common strategies such as seed-mediated growth, microemulsion methods, and surface functionalization to achieve precise size control. A recent systematic study by Makhadmeh et al. [4] provides important insights into tailored synthesis approaches for optimizing silica nanoparticles in biomedical applications. Finally, the article discusses current challenges, such as reproducibility and large-scale synthesis, and emphasizes future directions involving sustainable synthesis methods and predictive modelling.

Introduction Silica nanoparticles (SiNPs) have emerged as a promising platform in nanomedicine, particularly in the field of drug delivery. Their chemical stability, large surface area, tunable porosity, and biocompatibility make them suitable carriers for therapeutic molecules. A key determinant of their performance is particle size, as it influences biodistribution, cellular uptake, circulation time, and drug release efficiency [1–4]. Therefore, systematic control over nanoparticle size is fundamental to optimizing their function in biomedical applications.

Importance of Size in Drug Delivery

The biological fate of nanoparticles is largely governed by their dimensions. Particles smaller than 50 nm tend to penetrate tissues more deeply but are rapidly cleared by renal filtration. Larger particles (above 200 nm) often accumulate in the liver and spleen due to uptake by the reticuloendothelial system [2,4]. An optimal size range of 50–200 nm has been suggested for enhanced permeability and retention (EPR) in tumors, ensuring both efficient drug delivery and prolonged circulation [2–4]. Hence, tailoring the synthesis of SiNPs to achieve desired dimensions is crucial.

Key Parameters Affecting Silica Nanoparticle Size

Systematic studies of sol–gel synthesis methods, particularly the Stöber process, highlight several parameters that directly influence nanoparticle size [1,4]:

1. Precursor Concentration

The amount of tetraethyl orthosilicate (TEOS) directly affects nucleation and growth rates. Higher TEOS concentrations typically yield larger particles due to enhanced condensation [1].

2. Catalyst Type and Concentration

Ammonia is commonly used as a base catalyst. Increased ammonia concentration accelerates hydrolysis and condensation, often resulting in smaller, more uniform nanoparticles [1,4].

3. Solvent Composition

The ratio of ethanol to water modulates solubility and hydrolysis rates. Higher ethanol content usually leads to reduced particle size and better monodispersity [1,4].

4. Temperature

Elevated temperatures enhance reaction kinetics, which can either decrease or increase particle size depending on the balance between nucleation and growth [1–3].

5. Reaction Time

Prolonged synthesis allows continued growth of particles, leading to larger diameters unless growth is limited by precursor exhaustion [1].

Tailoring Strategies for Controlled Sizing

Researchers have developed systematic approaches to fine-tune particle size:

Seed-mediated growth: Small SiNPs are synthesized first and subsequently enlarged by controlled addition of precursors [2,4].

Microemulsion methods: Surfactants and co-surfactants stabilize nanodroplets, offering precise size control from 10–100 nm [2].

Surface functionalization: Modifying SiNPs with polymers or ligands can regulate growth and stabilize the desired size distribution [3,4].

Implications for Drug Delivery

Controlled particle sizing directly impacts therapeutic outcomes. For example, smaller nanoparticles enhance intracellular uptake, making them suitable for gene delivery or anticancer drugs requiring nuclear access [2–4]. Medium-sized particles are advantageous for passive tumor targeting via the EPR effect [2,3]. Additionally, uniformity in size distribution reduces aggregation and ensures predictable pharmacokinetics, both critical for clinical translation [4].

Challenges and Future Directions

Despite significant progress, several challenges remain. Reproducibility across large-scale synthesis is difficult due to sensitivity to minor changes in reaction conditions [1,4]. Moreover, size control must be balanced with other parameters such as porosity, surface charge, and functionalization [2,4]. Future research should focus on:

• Developing green synthesis routes with reduced chemical waste.
• Integrating machine learning models to predict optimal synthesis parameters.
• Conducting comprehensive in vivo studies to correlate particle size with therapeutic efficacy and safety [3,4].

Conclusion Silica nanoparticles hold enormous potential as drug delivery systems, but their success relies heavily on precise size control. Systematic investigations into synthesis parameters such as precursor concentration, catalyst level, solvent ratio, temperature, and time have provided valuable insights for tailoring nanoparticle dimensions [1,4]. Continued research in this area will advance the translation of SiNPs from laboratory studies to real-world clinical applications, ultimately improving the efficacy of modern drug delivery strategies [2–4].

References

1. Stöber, W., Fink, A., & Bohn, E. (1968). Controlled growth of monodisperse silica spheres in the micron size range. Journal of Colloid and Interface Science, 26(1), 62–69.

2. Tang, F., Li, L., & Chen, D. (2012). Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Advanced Materials, 24(12), 1504–1534.

3. Slowing, I. I., Vivero-Escoto, J. L., Wu, C. W., & Lin, V. S. Y. (2008). Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Advanced Drug Delivery Reviews, 60(11), 1278–1288.

4. Makhadmeh, G., Aljarrah, K., Al-Akhras, M. A. H., AlZoubi, T., Abuelsamen, A., Al Gharram, M., ... & AL-Diabat, A. M. (2025). Tailored size control of silica nanoparticles for drug delivery: A systematic study of synthesis parameters. Chemical Physics Impact, 100914.