Rational Design, Cross-Linking Engineering, and Disease-Specific Translation of Polymeric Gel Systems as Novel Drug Delivery Platforms: A Critical, Mechanistic Review of Advances from 2010 to 2026

Gel-based novel drug delivery systems (NDDS) occupy a mechanistically distinct niche among controlled-release platforms because they decouple three design variables—network cross-link density, continuous-phase polarity, and stimulus sensitivity—that in particulate carriers (liposomes, polymeric nanoparticles) are often interdependent. This critical review synthesizes 49 primary and secondary sources published predominantly between 2010 and 2026 to interrogate, rather than merely catalogue, how hydrogels, organogels, aerogels, nanogels, in situ gelling systems, and hydrogel-forming microneedles have been engineered for site-specific pharmacotherapy. Beyond a taxonomic overview, the review quantitatively contrasts formulation parameters—sol–gel transition temperatures (typically 32–37 °C for poloxamer 407/188 systems), swelling ratios, mesh sizes, and reported drug-release half-lives—across oncology, chronic diabetic wound care, ophthalmic and nasal-to-brain delivery, musculoskeletal (intra-articular) therapy, subunit vaccine depots, periodontal pocket therapy, and glucose-responsive insulin delivery. Particular attention is paid to the mechanistic basis of burst release, the porosity–mechanical-integrity trade-off inherent to interconnected hydrogel networks, and the divergence between preclinical rodent efficacy and the comparatively sparse controlled human trial data available for most gel platforms. The review concludes that while stimuli-responsive and 3D/4D-printed gel architectures have matured substantially as engineering constructs, clinical translation remains bottlenecked less by materials science than by inconsistent characterization standards, unresolved terminal-sterilization compatibility, and a paucity of head-to-head comparative trials against existing standard-of-care formulations.