Meropenem (MER) is one of the last resort antibiotics used to treat resistant bacterial infections. However, the clinical effectiveness of MER is hindered due to chemical instability in aqueous solution and gastric pH, and short plasma half-life. Herein, a novel multi-material delivery system based on γ-cyclodextrin (γ-CD) and poly lactic-co-glycolic acid (PLGA) is demonstrated to overcome these challenges. MER showed a saturated solubility of 14 mg/100 mL in liquid CO2 and later it was loaded into γ-CD to form the inclusion complex using the liquid CO2 method. The γ-CD and MER inclusion complex (MER-γ-CD) was encapsulated into PLGA by the well-established double emulsion solvent evaporation method. The formation of the inclusion complex was confirmed using FTIR, XRD, DSC, SEM, and 1H NMR and docking study. Further, MER-γ-CD loaded PLGA nanoparticles (MER-γ-CD NPs) were characterized by SEM, DLS, and FTIR. The drug loading and entrapment efficiency for MER-γ-CD were 21.9 and 92. 2% w/w, respectively. However, drug loading and entrapment efficiency of MER-γ-CD NPs was significantly lower at up to 3.6 and 42.1% w/w, respectively. In vitro release study showed that 23.6 and 27.4% of active (non-degraded drug) and total drug (both degraded and non-degraded drug) were released from MER-γ-CD NPs in 8 h, respectively. The apparent permeability coefficient (Papp) (A to B) for MER, MER-γ-CD, and MER-γ-CD NPs were 2.63 × 10-6 cm/s, 2.81 × 10-6 cm/s, and 2.92 × 10-6 cm/s, respectively. For secretory transport, the Papp (B to A) were 1.47 × 10-6 cm/s, 1.53 × 10-6 cm/s, and 1.58 × 10-6 cm/s for MER, MER-γ-CD and MER-γ-CD NPs, respectively. Finally, the MER-γ-CD inclusion complex and MER-γ-CD NPs retained MER’s antibacterial activities against Staphylococcus aureus and Pseudomonas aeruginosa. Overall, this work demonstrates the significance of MER-γ-CD NPs to protect MER from gastric pH with controlled drug release, while retaining MER’s antibacterial activity.

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