en Medical Pharmacology Medical Pharmacology Original Article Original Article <div style="text-align: justify;"><span style="font-size:12px;"><span style="font-family:Tahoma;"><span style="line-height:14.0pt"><span lang="EN">Resistance to monotherapies targeting receptor tyrosine kinases remains a major challenge in triple‑negative breast cancer (TNBC). Here, we developed a dual‑target HSA‑based<b> </b>nanobioconjugate combining human serum albumin (HSA)‑encapsulated Lapatinib&mdash;an EGFR1/2 inhibitor&mdash;with the VEGFR1/2‑blocking peptide VGB3 to achieve coordinated HER and VEGFR inhibition. Molecular docking predicted stable hydrogen‑bond and hydrophobic interactions between Lapatinib (free and HSA‑bound) and EGFR1/2, and between VGB3 and VEGFR1/2. HSA encapsulation enabled pH‑responsive, sustained drug release with faster kinetics under mildly acidic tumor conditions. Thermal denaturation assays confirmed increased conformational stability of HSA after binding, indicating structural integrity and biocompatibility. In vitro studies revealed that HSA‑Lapatinib exhibited a ~55 % reduction in IC₅₀ (from &asymp; 71 &micro;M to &asymp; 32 &micro;M) compared with free Lapatinib. The combination of 17 &micro;M HSA‑Lapatinib and 0.18 &micro;M VGB3 reduced cell viability to 25 % (CI = 0.29), confirming a strong synergistic effect. Flow‑cytometric analysis demonstrated a significant increase in apoptosis&mdash;from 40.8 % (HSA&ndash;Lapatinib) to 46.8 % (combination) (<i>P < 0.05</i>). RT‑PCR further showed a fourfold upregulation of <i>VEGFR2</i> (<i>P < 0.0001</i>), supporting that HSA‑Lapatinib triggers compensatory <i>VEGFR2</i> activation which is neutralized by VGB3. Collectively, these findings substantiate a mechanistic and quantitative synergy between HSA‑mediated HER inhibition and VGB3‑based VEGFR blockade. This dual‑target HSA‑Lapatinib/VGB3 system offers enhanced potency, reduced resistance, and a promising platform for precision‑guided TNBC therapy.</span></span></span></span></div> Triple-negative breast cancer, human serum albumin, Lapatinib, VEGFR2 upregulation, VGB3 peptide, Dual target therapy. 1031 1044 http://ijmcmed.org/browse.php?a_code=A-10-8730-1&slc_lang=en&sid=1 Sadegh Rostaminasab rostaminasabdolatabad@gmail.com 100319475328460036797 100319475328460036797 No Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran Sahar Memarkashani saharkashani765@gmail.com 100319475328460036798 0009-0000-8668-7675 No Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran tahereh rahdari taherehrahdari@yahoo.com 100319475328460036799 0009-0006-3545-7887 No Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. Seyed Mohsen Asghari sm.asghari@ut.ac.ir 100319475328460036800 100319475328460036800 Yes Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.