Development of Biocompatible Albumin Nanoparticles Using Sustainable Formulation Strategies

Serum albumins have attracted interest as biomaterials for the targeted delivery of compounds.^1,2 As endogenous proteins, albumins are biodegradable, exhibit low toxicity, and are available. Their structural flexibility can be exploited to develop stimuli-responsive delivery systems for controlled release at the target site.³ Albumin-based nanoparticles are commonly prepared by desolvation followed by chemical cross-linking, but organic solvents and synthetic cross-linking agents may raise toxicity concerns. ⁴ 

In this study, we optimized and characterized albumin-based nanoparticles (NPs) developed through sustainable preparation routes—conventional desolvation and metal-induced self-assembly—using ethanol as the desolvating agent and glucose as cross-linking (2:1 and 1:1 protein:glucose weight ratios). 

Bovine serum albumin (BSA)—commonly used as a model for human serum albumin (HSA)—and HSA were investigated to assess their influence on nanoparticle properties. Effects of albumin source and preparation method on size, polydispersity, surface charge, protein conformation and encapsulation efficiency were evaluated.  Desolvation yielded BSA NPs of 140 ± 10 nm at a 2:1 ratio and 120 ± 7 nm at 1:1, with 7% protein incorporation. Circular Dichroism confirmed retention of BSA’s native α-helical structure. Metal-assisted self-assembly (Cu²⁺) increased protein incorporation to 12% (2:1) and 14% (1:1), while CD revealed increased negative ellipticity at 222 nm, reflecting Cu²⁺-induced conformational rearrangements

Conversely, HSA yielded substantially larger nanoparticles via desolvation, 250 ± 20 nm (2:1) and 570 ± 20 nm (1:1). Cu²⁺ coordination resulted in uncontrolled aggregation and broad polydispersity, highlighting the limitations of considering BSA an interchangeable surrogate for HSA. Finally, quercetin encapsulation achieved 56% efficiency in desolvated BSA NPs and 65% in Cu²⁺-assembled BSA NPs. These results validate glucose-stabilized albumin nanocarriers while highlighting structural constraints.

[1] S. Gressler, C. Hipfinger, F. Part, A. Pavlicek, C. Zafiu, B. Giese, J. Nanobiotechnol. 23 (2025) 

[2] M.A. Beach, U. Nayanathara, Y. Gao, C. Zhang, Y. Xiong, Y. Wang, G.K. Such, Chem. Rev. 124 (2024)

[3] A. C. Egil, H. Kesim, B. Ustunkaya, Ö. Kutlu, G. Ozaydin Ince, J. Drug Deliv. Sci. Technol., 76 (2022),

[4] B. Bartlett, J.A. Klier, S. Razavi, Nanoscale 17 (2025)