Chitosan–Alginate Polyelectrolyte Systems: From Classical Release Models to the D‐PARMO Framework

ABSTRACT Despite the extensive preclinical optimization of biocompatible chitosan–alginate (CS/ALG) polyelectrolyte complexes for drug delivery, their clinical translation is hindered by a lack of predictive models linking formulation parameters to in vivo performance. This review bridges this “predictive gap” by critically deconstructing the physicochemical foundations of CS/ALG systems. We highlight the inadequacy of classical semi‐empirical models (e.g., Higuchi, Korsmeyer‐Peppas), which rely on descriptive curve‐fitting rather than a priori prediction. To overcome this, we introduce the Dual‐Polyelectrolyte Adaptive Release Mechanistic Outlook (D‐PARMO). This novel framework mechanistically unifies the key coupled phenomena governing release: dual‐polymer ionization equilibria, Flory‐Rehner swelling, Donnan partitioning, and multi‐modal transport kinetics. We condense this into an operational model that translates release data into physically meaningful parameters: a diffusion rate constant (k d ), erosion/swelling amplitude and rate (k e , k s ), and an electrostatic coupling coefficient (α). Comparative simulations demonstrate that D‐PARMO successfully identifies underlying physical drivers where classical models fail. Adopting this mechanistically informed operational framework provides a rational, science‐based pathway to support the design and de‐risk the translation of smart biomaterials.