Tailoring biodegradable polycaprolactone-polyethylene glycol coating on mesoporous silica nanoparticles: optimization of chain length for enhanced enzyme-triggered drug release in cancer therapy.

Poly(ε-caprolactone) (PCL) is a biodegradable polymer extensively explored for drug delivery applications, particularly in cancer therapy. However, tailoring its degradation kinetics is critical for designing efficient stimuli-responsive nanocarriers. In this study, we systematically optimized the chain length of PCL to construct a robust, enzyme-triggered, and actively targeted mesoporous silica nanoparticle (MSN) delivery system. A series of PCL variants with varying molecular weights were synthesized, and the ∼3100 Da chain was selected for its optimal balance of structural integrity and rapid enzymatic degradability. The chosen PCL was copolymerized with poly(ethylene glycol) (PEG) and folic acid (FA) to formulate a multi-functional corona, which was then grafted onto aminated MSNs to form the MSN-PCL-PEG-FA (MPPF) nanoplatform. Comprehensive characterizations confirmed the successful core-shell architecture, which functions as an enzyme-responsive polymeric gatekeeper. Acting as a compact hydrophobic barrier, this gatekeeper shell provided an excellent pore-capping effect that minimized premature doxorubicin (DOX) leakage under physiological conditions (pH 7.4). Crucially, the enzymatic degradation of this PCL gate in a tumor-mimicking environment (pH 5.0 with lipase) exhibited a synergistic release behavior, triggering a massive burst release (47.8%). In vitro studies on A549 cells demonstrated that folate receptor-mediated endocytosis significantly enhanced intracellular accumulation. Consequently, DOX@MPPF displayed superior dose-dependent cytotoxicity and a lower IC50 (∼2.2 ppm) compared to free DOX (∼6.46 ppm), indicating its capability to significantly improve therapeutic efficacy in an inherently chemo-tolerant cell line by maximizing intracellular drug retention. This rationally designed nanoplatform, with its tailored polymeric gatekeeper, holds great promise for precise and highly controlled cancer therapy.