Lung cancer remains one of the most lethal malignancies globally, underscoring the dire need for effective therapy. Scheduled administration of gemcitabine (GMC) followed by docetaxel (DTX) is clinically employed. Yet, the detrimental systemic toxicity and pharmacokinetic inadequacies such as the short plasma half-life of the former and poor bioavailability of the latter limit their use. Herein, we report the development of a novel inhalable nanocarrier system (NC) to enable the sequential release of drugs as per the clinical protocol. The developed NC has core-shell structure, with aminated mesoporous silica (MSNs) homing DTX at the core
enclosed within the polyanionic alginate (Alg) to prevent premature DTX release and serve as an intermediary sellotape layer. The outermost shell is polycationic as-synthesized PEGylated-chitosan (PEG-CS) loaded with GMC, to ensure stealth characteristics and prompt release of GMC. The newly developed PEG-CS/Alg@MSNs core-shell nanocarriers were comprehensively characterized. Besides it was evaluated in-vitro on A549 cell line and its in-vivo biodistribution was determined using jet nebulizer. Physicochemical analysis confirmed spherical core-shell NCs, 150 nm in size with +32 ± 1.5 mV surface charge. Drug entrapment efficiency was 75.2 ± 2.1 % for DTX and 32.5 ± 6.5 % for GMC, with sequential release in physiological conditions. Next Generation Impactor (NGI) experiments showed effective lung deposition with favorable aerosolization behavior. In-vitro assays on A549 cells revealed enhanced lung cancer treatment. In-vivo biodistribution confirmed lung accumulation, and histopathology indicated safety of NC. Conclusively, inhalable targeted NCs deem promising for lung cancer treatment.