<p>Lack of specificity, high toxicity, and low bioavailability are significant hurdles for conventional chemotherapies. Upregulated sialic acid receptors on the plasma membrane of lung cancer cells could be a promising target for effective drug delivery in the treatment of lung cancer. In this context, the present study aimed to fabricate sialic acid (SA)-conjugated epirubicin (Epi) and naringin (NA)-loaded silk fibroin (SF) nanoparticles (SA-Epi-NA-SF-NPs) for the selective delivery and enhanced treatment of lung cancer. SF protein was initially extracted from silk cocoons, and the SA-conjugated SF was synthesized using simple EDC-conjugation chemistry. Later, the desolvation cross-linking technique was used to fabricate SA-Epi-NA-SF-NPs by encapsulating Epi and NA into an SA-conjugated SF. The fabricated SA-Epi-NA-SF-NPs was nanosized, spherical, crystalline particles. Epi and NA had encapsulation efficiencies and loading capacities of 83 ± 1.5% and 80 ± 12%, respectively, and 8.34 ± 0.9% and 8.16 ± 0.3%, respectively, into SA-conjugated SF. Drug release was substantially higher at pH 5.4 (84.46 ± 1.29% Epi and 70.99 ± 1.56% NA) than at pH 7.4. The cytotoxic potential of SA-Epi-NA-SF-NPs against A549 cells was assessed by measuring viable cell number after 24&#xa0;h of treatment, with an IC₅₀ of 13.16&#xa0;µg×mL^− 1. This effect is attributed to the SA-conjugated NPs, which target A549 cells. The higher intracellular accumulation of Epi and NA in A549 cells targets both mitochondria and the nucleus, leading to apoptosis. Based on these outcomes, SA-Epi-NA-SF-NPs could be a beneficial approach for targeting and treating lung cancer cells, and may also open up research possibilities for targeting other tumor cells.</p>