Controlled reductive unfolding of BSA-α under pH stimuli and its supramolecular assembly with aminated gum acacia nanocarriers for targeted gemcitabine delivery in lung cancer therapy.

[UNLABELLED] In this work, we developed a pH-responsive and biocompatible nanocarrier system for targeted lung cancer therapy using bovine serum albumin-α (BSA-α)-functionalized aminated gum acacia (Am-GA) as a carrier for gemcitabine (GEM). The nanocarriers were formed through electrostatic and hydrogen-bonding interactions between the amine groups of Am-GA, the protein matrix of BSA-α, and the polar functional groups of GEM, which resulted in high drug encapsulation efficiency and good formulation stability. FTIR spectra of the developed nanocarriers showed noticeable changes in the amide and polysaccharide regions when compared with the individual components, indicating the presence of intermolecular interactions after formulation. From the XRD patterns, it was evident that gemcitabine lost its crystalline nature following encapsulation and appeared mainly in an amorphous form, a change that could favour better dissolution behaviour. Particle size measurements obtained from DLS showed that most of the particles were distributed within the range of ~120–180 nm. Zeta potential measurements indicated that the dispersion was stable, with no visible aggregation. TEM images showed mostly spherical particles with consistent morphology across the observed fields. Drug release studies demonstrated a clear pH-dependent pattern. At pH 7.4, the release of GEM from the BSA-Am-GA system remained low. When the pH was reduced to 5.5, the amount of released drug increased sharply. This behaviour is consistent with acidic tumour-like conditions. In A549 cells, the nanocarrier-treated groups showed stronger cytotoxic effects than free GEM. Higher cellular uptake was also observed. Apoptotic cell population increased under acidic conditions. ROS measurements indicated a noticeable rise in intracellular levels (~82.4%) after treatment with BSA-α-Am-GA@GEM. These observations point toward oxidative stress–related mitochondrial damage contributing to cell death. Furthermore, in vivo studies in A549 tumour-bearing BALB/c mice showed marked tumour volume regression with minimal systemic toxicity. This was supported by stable body weights and the preservation of normal histoarchitecture in major organs. Taken together, these findings indicate that naturally derived polymer–protein conjugates, such as the BSA-Am-GA system developed in this study, offer a promising strategy for engineering intelligent, tumour-specific nanoplatforms for advanced chemotherapeutic intervention in lung cancer.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13036-026-00631-2.