Background/Objectives: Poly(lactic-co-glycolic acid) (PLGA) microspheres are widely used in long-acting injectable (LAI) formulations because PLGA exhibits well-established biocompatibility and undergoes controlled hydrolytic degradation into metabolizable byproducts. However, optimization of microspheres typically requires time-consuming in vitro testing. Therefore, we developed a predictive machine learning model for early-stage and full time-dependent release profiles of drug-loaded PLGA microspheres. Methods: Using a published dataset comprising 321 release profiles from 89 drugs, we first developed a classification model to identify slow-release behavior (≤20% release within 3 days) and subsequently integrated the predicted early-release probability into a regression model to estimate cumulative release over time. Results: Among tree-based ensemble models, XGBoost achieved the lowest mean absolute error (MAE = 0.126) and highest Pearson correlation coefficient (r = 0.831). SHapley Additive exPlanations (SHAP) analysis revealed that drug and polymer molecular weight, predictive slow-release probability, and polymer concentration substantially influence release behavior. We also assessed this framework with external datasets. Drug release data for olaparib-loaded PLGA microspheres were obtained in-house, whereas those for semaglutide-based microspheres were obtained from the published literature. In both datasets, this framework demonstrated low MAE values (0.096 and 0.068, respectively). Conclusions: This suggests that the proposed framework can predict in vitro drug release and support efficient optimization of PLGA-based LAI formulations.

Oral administration remains the most convenient and favored route for systemic delivery of small-molecule drugs, primarily due to patient compliance and the absence of invasive procedures. Yet, poor aqueous solubility, chemical/enzymatic instability, and limited permeability in the gastrointestinal (GI) tract often result in low bioavailability (BA) of many therapeutic agents. Polymeric micelles formed from the self-assembly of amphiphilic block copolymers have gained considerable attention as a nanotechnology-driven solution to overcome these challenges. Their hydrophobic core–hydrophilic shell structure enables efficient encapsulation of poorly soluble small molecule drugs, providing protection from acidic or enzymatic degradation while potentially enhancing drug transport across the intestinal epithelium. This review examines the design principles, formulation strategies, and in vivo performance of polymeric micelles for oral delivery of small molecule drugs. We discuss strategies to improve micelle stability in the GI environment, including optimization of core hydrophobicity, kinetic stabilization, and corona engineering, and compare polymeric micelles with established alternatives such as self-micro emulsifying drug delivery system (SMEDDS) and amorphous solid dispersions (ASDs) across critical performance parameters. Despite decades of preclinical progress, no oral polymeric micelle formulation has reached regulatory approval, underscoring the persistent challenge of maintaining micellar structural integrity under the dynamic conditions of the GI environment. This review therefore examines not only the promise but also the structural vulnerabilities of oral micelles, proposing a stability-centered framework for interpreting micelle function under GI conditions. Finally, we discuss current translational challenges and suggest directions for future research toward clinical application of oral polymeric micelle systems.

Transdermal drug delivery is limited by the barrier function of the stratum corneum, which restricts the penetration of many therapeutic agents, whereas hypodermic injection provides efficient drug delivery but is associated with pain and reduced patient acceptability. Microneedle (MN) systems have therefore been investigated as a minimally invasive approach to overcome the stratum corneum and facilitate drug delivery into the skin. Among the materials used for MN fabrication, natural polysaccharides have attracted considerable attention because of their biocompatibility, biodegradability, aqueous processability, and diverse physicochemical properties. In addition, several polysaccharides, including chitosan, hyaluronic acid, and alginate, possess biological properties that may contribute to antimicrobial activity, tissue regeneration, or hemostasis. This review summarizes recent advances in natural polysaccharide-based MN systems, with emphasis on MN types, fabrication methods, material properties, and pharmaceutical applications. Dissolving, hydrogel-forming, and coated MNs are discussed together with fabrication approaches including micromolding, spray coating, and 3D/4D printing. The characteristics and representative applications of hyaluronic acid, chondroitin sulfate, starch, chitosan, cellulose derivatives, alginate, pullulan, dextran, and Bletilla striata polysaccharide are reviewed, including their use in insulin delivery, vaccination, cancer therapy, dermatological treatment, and wound healing. Finally, current challenges related to mechanical strength, dissolution behavior, drug loading and uniformity, raw-material variability, moisture sensitivity, manufacturing scalability, and regulatory translation are discussed. Further development of standardized evaluation methods and reproducible manufacturing processes will be important for the pharmaceutical translation of natural polysaccharide-based MN systems.