(PA) is an opportunistic pathogen, which causes serious lung infections in immunocompromised patients. Traditional oral intake of large quantities of small-molecule antibiotics to treat bacterial infections leads to off-target toxicity and development of drug-resistant species. Improved delivery systems of antibiotics to the targeted site of bacterial infections would help reduce the need for a high intake of antibiotics. Colistin (Col), an antibacterial peptide, is considered the last resort treatment for multidrug resistant (MDR)-PA. To approach the problem of development of antibacterial resistance and off-target toxicity due to the use of excessive amounts of antibiotics, we have designed a targeted drug delivery nanoassembly, which delivers antibiotics to extracellular and intracellular bacteria. The nanoassembly is composed of (1) drug (Col)-loaded mesoporous silica (MSN) core (Col@MSN), (2) liposomal shell (Col@MSN@LL), and (3) PA-targeting LL-37 peptide (Col@MSN@LL-(LL-37)). The liposomal shell prevents premature drug release before the nanoassembly approaches the targeted bacteria. The liposome bilayer degrades upon excreted lipase present in the local environment of PA, releasing encapsulated Col. There is a significant increase in Col release (∼90% release within 40 h) in the presence of bacteria compared to the absence of bacteria (only ∼75% release after 80 h). A 6.7-fold increase in the antimicrobial efficacy of Col encapsulated in Col@MSN@LL-(LL-37) was seen compared to free Col. All studies were done using a clinical strain of PA14. Col@MSN@LL-(LL-37) successfully targets and inhibits intracellular PA14 within the lung epithelial cells. Only 7% PA14 viability is seen after treating the lung epithelial cells with Col@MSN@LL-(LL-37). No significant cytotoxicity was observed with Col@MSN@LL-(LL-37). Therefore, this discussed lipid-coated targeted nanoassembly can be considered as a successful antibiotic delivery platform.