Pulmonary delivery of drug nanocarriers can overcome the shortcomings of systemic cancer therapy via the enhanced permeability and retention (EPR) based-nanomedicine. Herein, inhalable multi-compartmental nanocomposites with the capability for both localized and modulated release of the hydrophobic mTOR inhibitor, rapamycin (RAP) and the hydrophilic herbal drug, berberine (BER) have been developed for lung cancer therapy. Two types of multi-compartmental nanocarriers were fabricated by enveloping BER hydrophobic ion pair-lipid nanocore within a shell of RAP-phospholipid complex bilayer to reduce the delivery gap between the two drugs. To further enhance their tumor targeting, the nanocarriers were layer-by-layer coated by cationic lactoferrin and anionic hyaluronate resulting in enhanced internalization and cytotoxicity against lung cancer cells. The inhalable nanocomposites fabricated by spray-drying of multi-compartmental nanocarriers exhibited favorable aerosolization efficiency (MMAD of 3.28μm and FPF of 55.5%). The powerful anti-cancer efficacy of inhalable nanocomposites in lung cancer bearing mice compared to the inhaled free drugs was revealed by remarkable decrease in lung weight, and reduction in both number and diameters of lung adenomatous foci and angiogenic markers compared to positive control. Overall, localized delivery of RAP and BER to tumor cells via inhalable multi-compartmental nanocomposites holds great promise in management of lung cancer.