Beyond Nanosizing: Mechanism-Guided Design and Rational Selection of Polymeric and Lipid Nanocarriers for Translatable Drug Delivery.

BACKGROUND

Nanosizing can modify dissolution and carrier behaviour, but particle size alone does not determine clinically useful exposure.

OBJECTIVE

To compare polymeric and lipid-based nanocarriers using a mechanism-guided framework that links payload properties, composition, process conditions, biological barriers, critical quality attributes (CQAs), and translational risk.

METHODS

A critical narrative review with a structured scoping update was performed using PubMed, Scopus, Web of Science, and Google Scholar during manuscript preparation. The intended publication window was 2010-2025, with earlier seminal studies retained where mechanistically necessary. Because exact search dates, an auditable database export, screening counts, and independent-reviewer records were not preserved, this review is not presented as a systematic review and no pooled effect estimate is reported.

RESULTS

Polymeric systems can stabilize selected amorphous or molecularly dispersed payloads and tune release through diffusion, hydration, and degradation, whereas lipid systems can support lipid-phase solubilization, digestion-dependent oral absorption, membrane interaction, and nucleic-acid delivery. Across both classes, precipitation, release failure, phase transformation, protein-corona and immune effects, endosomal sequestration, and process drift can disconnect favorable in vitro attributes from human pharmacology. Clinical examples show product-specific changes in disposition, safety, or efficacy rather than a universal bioavailability multiplier.

CONCLUSION

Rational nanocarrier selection should start from a testable mechanism and a defined translational risk, then be challenged with route-relevant biological assays, exposure measurements, safety data, and manufacturing comparability. The proposed framework is hypothesis-generating and requires prospective validation.