β-Sitosterol–Naringenin Co-Loaded Nanophytosomes: Encapsulation, Compound-Specific Release Kinetics, Machine Learning-Assisted Release Prediction, and Cell-Dependent Anticancer Activity

β-Sitosterol and naringenin have anticancer potential but poor biopharmaceutical properties, while their behavior when co-encapsulated remains poorly defined. This study examined whether co-loading alters encapsulation efficiency, compound-specific release behavior, predictability, and cell-dependent activity. Single- and co-loaded nanophytosomes were characterized for encapsulation and release. Release profiles underwent comparative kinetic modelling, uncertainty-aware augmentation, early-to-late ridge-regression forecasting, Weibull-parameter reconstruction, and exploratory reconstructed-replicate holdout assessment. Cytotoxicity was assessed in A549 (ATCC CCL-185), HCT116 (ATCC CCL-247), and HEK293 (ATCC CRL-1573) cells, with docking against MEK1, COX-2, and PI3Kα. Co-loading increased β-sitosterol encapsulation from 5.92% to 66.61% but reduced naringenin encapsulation from 89.76% to 40.40% (p = 0.02), the co-loaded formulation also exhibited the smallest vesicles (132.7 ± 3.2 nm). At 48 h, release reached 87.30% and 73.24%, respectively; Weibull best described β-sitosterol and Higuchi naringenin, revealing asynchronous release and a time-dependent delivery ratio. Across 1200 augmented profiles, first-4-h measurements predicted 6–48-h release with R2 = 0.976–0.996, while parameter-based reconstruction reproduced compound-specific trajectories. Exploratory reconstructed-replicate assessment yielded a pooled R2 of 0.938 (mean absolute error (MAE) = 3.32%; root-mean-square error (RMSE) = 4.78%). The co-loaded formulation showed its strongest relative activity in A549 cells and better preserved HEK293 viability than the free combination, whereas the free combination was more active in HCT116 cells. Naringenin docked across all targets (7.58 to −8.40 kcal/mol), whereas β-sitosterol showed weaker binding and no COX-2 pose. Co-loading was associated with opposing encapsulation trends, while the resulting formulation exhibited compound-specific release kinetics and cell-dependent responses rather than uniformly enhanced activity. Integrating physicochemical characterization, kinetic discrimination, predictive modelling, docking, and cell testing provides a multidimensional framework for dual-bioactive nanophytosomes.