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Conjugated polymer nanoparticles (CPNs) doped with porphyrins, such as platinum porphyrin\u2013doped poly(9,9-dioctylfluorene-alt-benzothiadiazole) (F8BT), exhibit enhanced photodynamic efficiency but lack comprehensive preclinical toxicity data. This study aimed to evaluate the biocompatibility, biodistribution, and acute\/subacute toxicity of these CPNs to establish their safety profile for clinical translation. Methods: CPNs were synthesized via nanoprecipitation using amphiphilic stabilizers (PSMA or PS-PEG-COOH) and characterized for colloidal stability in parenteral solutions. Hemolysis assays were used to assess blood compatibility. Single-dose (0.3 and 1 mg\/kg, intravenous) and repeated-dose (0.1\u20131 mg\/kg, intraperitoneal, every 48 h for 28 days) toxicity studies were conducted in BALB\/c mice. Hematological, biochemical, histopathological, and biodistribution analyses (via ICP-MS) were performed to evaluate systemic and organ-specific effects. Results: CPNs demonstrated excellent colloidal stability in 5% dextrose, with minimal aggregation. No hemolytic activity was observed at concentrations up to 50 mg\/L. Single and repeated administrations revealed no significant changes in body\/organ weights, hematological parameters (except transient fibrinogen elevation), or liver\/kidney function markers (ALT, AST, BUN, Cr). Histopathology showed preserved tissue architecture in major organs, with mild hepatocyte vacuolation at 30 days. Biodistribution indicated hepatic\/splenic accumulation and rapid blood clearance, suggesting hepatobiliary elimination. Conclusions: Platinum porphyrin\u2013doped F8BT CPNs exhibited minimal acute and subacute toxicity, favorable biocompatibility, and no systemic adverse effects in murine models. These findings support their potential as safe PS candidates for PDT. However, chronic toxicity studies are warranted to address long-term organ accumulation and metabolic impacts. This preclinical evaluation provides a critical foundation for advancing CPNs toward clinical applications in oncology.<\/jats:p>","DOI":"10.3390\/pharmaceutics17050593","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T08:28:11Z","timestamp":1746174491000},"page":"593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Preclinical Toxicological Characterization of Porphyrin-Doped Conjugated Polymer Nanoparticles for Photodynamic Therapy"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7362-2770","authenticated-orcid":false,"given":"Mat\u00edas Daniel","family":"Caverzan","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones en Tecnolog\u00edas Energ\u00e9ticas y Materiales Avanzados (IITEMA), Universidad Nacional de R\u00edo Cuarto (UNRC) y Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), R\u00edo Cuarto X5800BIA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Bel\u00e9n","family":"Morales Vasconsuelo","sequence":"additional","affiliation":[{"name":"Instituto de Biotecnolog\u00eda Ambiental y Salud (INBIAS), Universidad Nacional de R\u00edo Cuarto (UNRC) y Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Rio Cuarto X5800BIA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Cerchia","sequence":"additional","affiliation":[{"name":"Institute of Endotypes in Oncology, Metabolism and Immunology \u201cGaetano Salvatore\u201d, National Research Council, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo Emiliano","family":"Palacios","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones en Tecnolog\u00edas Energ\u00e9ticas y Materiales Avanzados (IITEMA), Universidad Nacional de R\u00edo Cuarto (UNRC) y Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), R\u00edo Cuarto X5800BIA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Alberto","family":"Chesta","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones en Tecnolog\u00edas Energ\u00e9ticas y Materiales Avanzados (IITEMA), Universidad Nacional de R\u00edo Cuarto (UNRC) y Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), R\u00edo Cuarto X5800BIA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6077-7992","authenticated-orcid":false,"given":"Luis Exequiel","family":"Ibarra","sequence":"additional","affiliation":[{"name":"Instituto de Biotecnolog\u00eda Ambiental y Salud (INBIAS), Universidad Nacional de R\u00edo Cuarto (UNRC) y Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Rio Cuarto X5800BIA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1002\/jnr.24776","article-title":"Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events","volume":"99","author":"Ibarra","year":"2021","journal-title":"J. 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