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Abstract Background Lung cancer remains a leading cancer type, but current chemotherapy is limited by issues including poor drug delivery, toxicity, and resistance. To address these challenges, we developed a novel PLGA-PEG-LHRH (PPL) nanoconjugate system for improved drug delivery. Curcumin, known for its anticancer and P-gp inhibition properties, was co-loaded with bcl2siRNA (bclsR) to inhibit the bcl2 protein, thus overcoming both resistance mechanisms. Results The PPL conjugate was successfully synthesized and characterized using FTIR, 1H NMR, XRD, XPS and BCA assay. Curcumin and bclsR-loaded PLGA nanoemulsions were prepared by double emulsion solvent evaporation method and characterized. The optimized nanoconjugate had size of 179 ± 16 nm, favorable zeta potential, high drug entrapment, and was confirmed via TEM. Controlled release studies indicated 83% drug release within 24 h. In vitro studies revealed significant cytotoxicity against A549 lung cancer cells, with the nanoconjugate showing IC50 of 8.24 µg/mL compared to 21.26 µg/mL for plain curcumin. Enhanced cellular uptake and effective targeting of A549 cells were observed. Molecular analyses demonstrated significant downregulation of MDR1 and Bcl2 RNA and protein expression, highlighting the nanoconjugates' ability to suppress resistance mechanisms. Pharmacokinetic studies in Wistar rats showed superior plasma drug concentrations, half-life, and AUC for the nanoconjugate versus pure drug suspension. Biodistribution studies showed increased drug accumulation in the lungs. In vivo efficacy studies in Balb/c mice demonstrated higher tumor inhibition ratios for CUR-siRNA PPL NPs (66.89%) and CUR-PPL NPs (59.84%) which was further confirmed with TNFα and p53 levels in blood. Histopathological studies showed good healing in the CUR-siRNA PPL NP- and CUR-PPL NP-treated mice compared to suspension. Conclusion From the study, it may be concluded that the PPL nanoconjugate system, loaded with curcumin and bcsR, can be potentially effective, multifunctional targeted approach for lung cancer therapy. Graphical Abstract

Despite various efforts, a successful selective delivery system for chemotherapeutic agents for lung cancer is still lacking. Dry powder inhaler (DPI) systems based on proliposomes (PLMs) could be a potential system for the efficient delivery of paclitaxel to lungs. PLM-based DPI prepared with a freeze-drying method can therefore be an alternative. Paclitaxel-loaded PLM-based DPI (PTX-PLM-DPI) powders were prepared using the method of thin film deposition on a carrier followed by freeze drying. These were prepared using soya phosphatidylcholine (SPC) and cholesterol as the lipids and mannitol as the carrier. The reconstituted liposomes were evaluated in terms of size, morphology, drug entrapment, release and cytotoxicity. The DPI powders were evaluated for their flow property, surface topography, dose uniformity and in vitro lung deposition. Stable and free-flowing PTX-PLM-DPI powder was obtained that could be reconstituted into homogenous liposomal vesicles < 200 nm as confirmed by TEM and SEM studies. The liposomes showed drug entrapment of 92.64 ± 1.4% and diffusion-controlled release of up to 28% in 24 h. These liposomes showed better dose-dependent cytotoxicity in A549 cells in comparison to paclitaxel suspension with IC50 values of 46 ± 0.87 ng/mL and 154.9 ± 3.64 ng/mL, respectively. In vitro lung deposition studies of the PTX-PLM-DPI showed sufficient deposition with the fine particle fraction (FPF) of 50.86 ± 2.8% of particles with an aerodynamic diameter less than 5 µ. Hence, it canbe concluded that PLM-based DPI prepared by freeze drying can be a promising, stable, safe and free-flowing system for the enhanced lung delivery of paclitaxel.