Porous silicon nanoparticles in drug delivery, regenerative medicine, and biosensing: a translational review

Porous silicon nanoparticles (pSiNPs) have become a versatile platform for biomedical applications owing to their tunable pore structure, high surface area (200-800 m²/g), intrinsic biodegradability into orthosilicic acid, and versatile surface chemistry. This review systematically examines the synthesis strategies (electrochemical etching, magnesiothermic reduction, stain etching, laser ablation), composite fabrication with biocompatible polymers (PCL, PLGA, chitosan, PEG), and surface functionalization approaches that govern pSiNP performance in biological environments. We evaluate preclinical evidence across four major application domains: (i) targeted drug delivery, where pH-responsive and MMP-cleavable gating strategies have demonstrated up to 7-fold lower off-target toxicity in murine tumor models; (ii) regenerative medicine, including non-load-bearing bone repair (2.1-2.3-fold increase in BV/TV in rodent calvarial defects) and chronic wound healing (95% wound closure by day 14 in diabetic mice); (iii) implant surface modification, with pSiNP coatings improving osseointegration and reducing capsular contracture in rabbit models; and (iv) biosensing and imaging, achieving fM-pM detection limits and tumor-to-background ratios >8:1. Despite these advances, all current evidence remains at the in vitro or preclinical stage; no pSiNP-based product has entered clinical trials. Critical barriers to translation include batch-to-batch manufacturing variability, unpredictable in vivo degradation kinetics, mechanical fragility under load-bearing conditions, and the absence of harmonized regulatory standards for combination products. We propose a three-pillar framework-predictive in vitro-in vivo correlation, modular surface engineering, and GMP-compliant manufacturing-as a roadmap toward rational clinical development.