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However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP\/siRNAGEM) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNAGEM was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP\/siRNAGEM is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP\/siRNAGEM exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX\/GEM\/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs.<\/jats:p>","DOI":"10.3390\/nano14201657","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T09:14:48Z","timestamp":1729242888000},"page":"1657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeted PHA Microsphere-Loaded Triple-Drug System with Sustained Drug Release for Synergistic Chemotherapy and Gene Therapy"],"prefix":"10.3390","volume":"14","author":[{"given":"Shuo","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Life Science, Hengshui University, Hengshui 053000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huandi","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyu","family":"Fan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangqing","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7806-6814","authenticated-orcid":false,"given":"Honglei","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Guo, S.X., Chen, M.Q., Li, S.Y., Geng, Z.J., Jin, Y., and Liu, D. 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