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Direct oral intervention of spleen aminopeptide (SA) would be limited because of its varied swelling and release rate in different pH environments of digestive fluids. Herein, pH-responsive hydrogel microspheres (3.67 ± 0.04 mm) with positive SA-loaded chitosan (Cs) core and negative alginate (ALG) shell were prepared. Entrapment efficiency was 76.22% and loading rate of SA was 35.17%. Besides the hydrogen bonding, a strong core/shell structure was constructed by forming imine bond via the Schiff base reaction of amino group in Cs with ketone group on SA. In vitro simulated digestion showed that the swelling rate of microspheres was 192.8% (pH 1.2), 2481.5% (pH 6.8), and 1144.3% (pH 7.4). The release rate of SA was 0.9% in simulated gastric fluid for 2 h, 6.0% in simulated intestinal fluid for 2 h and continuous release in simulated colonic fluid for 24 h with a cumulative release rate of 92.4%. After treatment, the observation group exhibited increasing levels of CD3⁺, CD4⁺, CD4⁺/CD8⁺, IgA, IgG and IgM. Total effective rate in observation group was 96.15%, being higher than that in control group (84.31%). This work provided a valuable reference for preparing drug-loaded hydrogels to improve the recurrent respiratory infection in children.