Folate-targeted pH-sensitive albumin nanoparticles loaded with Baicalin enhance tamoxifen efficacy and overcome drug resistance in estrogen receptor alpha-positive breast cancer

To address tamoxifen (TAM) resistance in estrogen receptor α (ERα)-positive breast cancer and enhance the bio availability of baicalin (BA), this research developed pH/folate dual-responsive bovine serum albumin (BSA)-based nanoparticles (NPs) to improve TAM sensitivity. Four BA-loaded BSA NPs were engineered: non-targeted (BA@BSA NPs), folate-targeted (BA@FA BSA NPs), pH-sensitive (BA@mPEGA BSA NPs), and dual-responsive (BA@mPEGA FA BSA NPs). Physicochemical characterization included TEM, dynamic light scattering (size, PDI, zeta potential), encapsulation efficiency, drug loading, FTIR, TGA and stability. pH-dependent drug release profiles (pH 5.0, 6.5, 7.4) were evaluated. Cellular uptake (fluorescence imaging via FRα targeting) and cytotoxicity (pH 6.5 vs. 7.4) were assessed in TAM-resistant LCC9 cells. In vivo efficacy was determined through hemocompatibility, tumor-targeting efficiency (fluorescence imaging), and xenograft tumor suppression. Four BA-loaded BSA NPs exhibited uniform morphology (80–120 nm), low PDI (<0.2), negative zeta potential (−13 to −16 mV), high encapsulation efficiency (>85 %), and drug loading (>0.5 %). FTIR confirmed successful fabrication. BA@mPEGA FA BSA NPs showed superior thermal stability (1.29 % mass loss at 40–110 °C vs. 1.73–4.23 % for other four BA-loaded BSA NPs),the nanoparticles demonstrated good stability when stored at 4 °C for three months and pH-responsive BA release (87.74 ± 0.55 % at pH 5.0 vs. 58.11 ± 1.18 % at pH 6.5 and 14.81 ± 1.58 % at pH 7.4 over 48 h). Combined with TAM, BA@mPEGA FA BSA NPs reduced LCC9 cell IC 50 by 2.29-fold (pH 6.5) versus free BA+TAM.FRα-mediated BA@mPEGA FA BSA NPs cellular uptake was 7.20-fold higher than free FA + BA@mPEGA FA BSA NPs ( p  < 0.0001). In vivo, NPs showed low hemolysis (<5 %) and tumor targeting. BA@mPEGA FA BSA NPs MD+ TAM achieved 82.06 ± 3.67 % tumor suppression, significantly outperforming controls (p < 0.0001), and demonstrated favorable safety profiles. The dual-responsive BA@mPEGA FA BSA NPs effectively overcome BA delivery limitations and resensitize ERα + breast cancer to TAM, offering a clinically translatable strategy to combat endocrine therapy resistance.