Alginate is an anionic polysaccharide found in brown algae that have been utilized for encapsulation to produce a sustained- or controlled-release form of drug dosage. The sustained release of drugs facilitated by alginate-based nanocarriers is one of the attractive aspects of alginate use since these nanocarriers might allow the drug to be continuously and slowly released into the body. This study was conducted to investigate drug-encapsulating alginate nanoparticles by curating scientific answers for the outcomes of different synthetic approaches, such as the utilization of different cross-linkers and their mixtures. Thus, we optimized the prepared formulation using Minitab software 18.1 at the highest loading efficiency, smallest particle size, and highest absolute zeta potential. Moreover, we used the Plackett-Burman experimental design through the Minitab 18.1 statistical program to study the influences of independent variables (concentration of sodium alginate, cromolyn, aluminum chloride, and ferric chloride) on the loading efficiency, particle size, and zeta potential. This work involved the preparation of a cromolyn-nanocomposite (Cromo-Alg-NPs) using Al+3 and Fe+3 cross-linkers. The Placket-Burman design was used to prepare twenty-eight formulations with four independent variables at two levels of Al+3, Fe+3, cromolyn, and polymer. Three response measures were used in this study: loading efficiency, particle size, and zeta potential. A response surface model was used to analyze the data by means of graphical analysis, surface, contour, and main effect charting, Pareto charting, normal probability plotting, and residual-against-corresponding anticipated values plotting. Furthermore, the current study compared experimentally obtained results and predicted values using bias values. The bias value indicate that the generated models were valid and efficient, with a good correlation between the predicted and experimental values and no statistically significant differences. The vibrational frequencies of pure cromolyn, Alg-NPs, and Cromo-Alg-NPs nanocomposites were characterized using FTIR, which was used to identify the essential functional groups of Cromo-Alg-NPs nanocomposites. The release of Cromo from Cromo-Alg-NPs nanocomposites was studied at pH 7.4, the results indicated that the release occurred up until 120 minutes, and the completed release was obtained after 350 minutes.