Polycaprolactone (PCL) nanoparticles have gained significant attention in biomedical applications due to their slow degradation kinetics, making them ideal for long-term therapeutic delivery and tissue engineering. Unlike faster-degrading polymers such as poly(lactic-co-glycolic acid) (PLGA), PCL exhibits prolonged stability under physiological conditions, enabling sustained release of therapeutics over weeks to months. This property is particularly advantageous for implantable drug depots or scaffolds requiring mechanical integrity during tissue regeneration. The following discussion explores PCL nanoparticle fabrication methods, degradation behavior, mechanical stability, and comparative advantages over PLGA.

Fabrication of PCL nanoparticles commonly employs melt-emulsification and electrospraying techniques. Melt-emulsification involves dissolving PCL in a molten state, followed by dispersion in an aqueous surfactant solution under high shear forces to form nano-sized droplets. Upon cooling, these droplets solidify into nanoparticles with controlled size distributions, typically ranging from 100 to 500 nm. The process parameters, including temperature, surfactant concentration, and shear rate, influence particle size and morphology. Electrospraying, an alternative method, utilizes high-voltage electric fields to atomize PCL solutions into fine droplets, which solidify into nanoparticles upon solvent evaporation. This technique offers precise control over particle size and shape, with diameters adjustable between 50 nm and several micrometers. Both methods yield nanoparticles with high encapsulation efficiency for hydrophobic drugs, owing to PCL’s semi-crystalline and hydrophobic nature.

Mechanical stability under physiological conditions is a critical factor for PCL nanoparticles in long-term applications. PCL’s semi-crystalline structure provides robust mechanical properties, maintaining structural integrity in aqueous environments. The polymer’s glass transition temperature (Tg) of approximately -60°C ensures flexibility at body temperature, while its melting point (Tm) around 60°C prevents premature deformation. Studies indicate that PCL nanoparticles retain their morphology and drug payload under physiological shear stresses, such as those encountered in circulation or within tissue matrices. This stability contrasts with PLGA nanoparticles, which may undergo rapid plasticization and deformation due to water absorption and hydrolysis-induced softening.

Degradation of PCL occurs primarily through bulk hydrolysis of ester bonds, a process significantly slower than surface erosion mechanisms seen in PLGA. In vivo, PCL degradation proceeds in two stages: initial non-enzymatic hydrolysis, followed by enzymatic cleavage by lipases and esterases. The first stage involves random scission of polymer chains, reducing molecular weight without immediate mass loss. This phase can span several months, depending on PCL’s initial molecular weight and crystallinity. For instance, high-molecular-weight PCL (80,000–100,000 Da) may take 2–3 years for complete resorption, while low-molecular-weight variants (10,000–20,000 Da) degrade within 12–24 months. The second stage involves macrophage-mediated phagocytosis and enzymatic breakdown, culminating in the metabolization of degradation byproducts into carbon dioxide and water via the Krebs cycle.

Comparative analysis with PLGA highlights PCL’s suitability for extended-release applications. PLGA degrades within weeks to months, with rates adjustable via lactic-to-glycolic acid ratios but invariably faster than PCL. For example, PLGA 50:50 (50% lactic acid, 50% glycolic acid) degrades within 1–2 months, while PLGA 85:15 may require 5–6 months. This rapid degradation often leads to burst release of encapsulated drugs, limiting utility for sustained delivery. In contrast, PCL’s slower degradation enables linear release kinetics, ideal for therapies requiring steady drug levels over prolonged periods. Additionally, PLGA’s acidic degradation byproducts may provoke localized inflammation, whereas PCL’s neutral metabolites exhibit superior biocompatibility.

In tissue engineering, PCL nanoparticles serve as durable scaffolds or carriers for growth factors. Their slow degradation aligns with the extended timelines of tissue regeneration, particularly in bone or cartilage repair, where mechanical support is needed for months. Electrospun PCL nanofibers, for instance, demonstrate tensile strengths of 2–4 MPa, sufficient for load-bearing applications. The gradual release of osteogenic or chondrogenic factors from PCL nanoparticles further enhances tissue maturation without frequent re-administration.

In summary, PCL nanoparticles offer distinct advantages for long-term therapeutic applications due to their slow degradation, mechanical resilience, and biocompatibility. Fabrication via melt-emulsification or electrospraying allows tailored particle characteristics, while their hydrolysis-resistant structure ensures prolonged functionality in physiological environments. Compared to PLGA, PCL provides superior sustainability for drug delivery and tissue engineering, making it a preferred choice for implantable depots and regenerative medicine. Future research may focus on optimizing degradation rates through copolymerization or surface modifications while retaining PCL’s inherent stability.