Search Results (4,004)

Caffeic acid (CA) is a phenolic compound commonly found in fruits, vegetables, and coffee, with preclinical evidence demonstrating its important role in disease management through different mechanisms of action. This review aimed to explore CA’s pharmacological effects in different pathological conditions, and sources were retrieved by using databases like PubMed, Scopus, Google Scholar, and Web of Science and based on preclinical studies. CA notably protects cells and tissues from oxidative stress and inflammation, highlighting its therapeutic role in the management of pathogenesis. The neuroprotective, cardioprotective, hepatoprotective, anti-microbial, and anti-obesity effects are reported through in vitro and in vivo studies. Moreover, its anticancer effects are linked to modulation of cell signaling pathways, together with angiogenesis, cell cycle, apoptosis, and the PI3K/Akt pathway. This article explores how caffeic acid influences health conditions, providing a comprehensive overview of its effects on disease processes. Reviewing the literature aims to enhance the understanding of caffeic acid’s role in disease management and as a natural therapeutic agent. Although several studies demonstrate the anticancer effects and its role in the management of various pathological conditions, most of the existing evidence is based on in vitro, in vivo, and xenograft models. Moreover, many natural compounds, including CA, that exhibit activity in preclinical settings fail to translate into clinical applications, due to restrictions of poor bioavailability, toxicity, rapid metabolism, and differences in the tumor microenvironment. Thus, future studies should emphasize well-designed in vivo studies as well as controlled clinical trials to better describe CA’s safety, efficacy, mechanism of action, and therapeutic application in humans. Further investigation of its interactions with other therapeutic agents may offer insights into synergistic effects that enhance treatment efficacy. Overall, a more comprehensive understanding of this compound will be indispensable for its development as a therapeutic agent in the treatment of chronic disease. Full article

Background: Adipocytes play a critical role in the breast cancer tumorigenic microenvironment. However, their effects and underlying mechanisms remain unclear. This study aims to investigate the role of adipocytes in luminal A breast cancer invasiveness at the cellular and molecular levels. Methods: Various adipocyte types were co-cultured with MCF7 breast cancer cells in direct and indirect manners. Invasiveness was assessed via proliferation, migration, and invasion, with alterations examined at morphological, cellular, and molecular levels. The role of adipocytes on MCF7 was further explored using an orthotopic breast cancer xenograft mouse model. Results: MCF7 co-cultured with adipocytes, especially brown adipocytes (BAC), showed increased invasiveness and tumorigenic potential. Morphologically, co-cultivation with BAC increased the proliferation, EMT, and stemness of MCF7. Mechanistically, co-culture of MCF7 with BAC exhibited disturbed expression of genes related to adipogenesis and mitochondrial dynamics; notably, IRX3 was the most prominently elevated one. Knockdown of IRX3 restored balanced mitochondrial function and reduced both the invasiveness of breast cancer cells in vitro and tumor growth in vivo. Conclusions: Brown adipocytes promote breast cancer invasiveness by upregulating adipogenesis-related IRX3, which acts via the mitochondrial functional regulation. Full article

Prostate cancer (PCa) is the second most frequently diagnosed solid malignancy in men and a major cause of cancer-related mortality worldwide. While localized disease is associated with excellent long-term survival, advanced and castration-resistant PCa continues to represent a major therapeutic challenge. Current management ranges from active surveillance for indolent tumors to multimodal systemic approaches for metastatic disease. In this context, natural compounds are attracting increasing interest as adjunctive or novel therapeutic agents. Among these, silymarin, a Silybum marianum-derived flavonolignan complex, has shown promising antineoplastic activity in preclinical PCa models. In vitro, silymarin compounds consistently inhibit PCa cell proliferation by inducing G1 and G2/M cell cycle arrest, upregulating cyclin-dependent kinase inhibitors, and activating caspase-dependent apoptotic pathways. They also modulate key oncogenic signaling pathways involved in cell survival, proliferation, invasion, and metastasis. In vivo xenograft and transgenic models further show reduced tumor growth, angiogenesis, and metastatic spread with limited systemic toxicity. Emerging clinical evidence, including systematic reviews and meta-analyses, suggests translational potential; however, robust randomized trials are needed to define optimal formulations, dosing strategies, and therapeutic efficacy in PCa patients. This review provides a comprehensive overview of the molecular mechanisms, preclinical efficacy, and emerging clinical evidence supporting silymarin as a candidate for future PCa research. Full article

(1) Background: The role of baseline humoral immunization in bone regeneration remains unclear. This study assessed the relationship between baseline serological immunization, graft type, photobiomodulation (PBM), and histological outcomes after maxillary sinus floor augmentation. (2) Methods: This exploratory secondary analysis included 20 adults undergoing lateral maxillary sinus lifting. Patients were allocated according to graft type (allogeneic or xenogeneic) and postoperative protocol (with or without adjunctive PBM). Before surgery, serum samples were analyzed for anti-HLA class I, anti-HLA class II, and anti-MICA antibodies. After approximately 6 months, bone core biopsies were collected. Histological evaluation focused on inflammatory cell infiltrates (ICI). (3) Results: Baseline antibody positivity was detected in 35.0% of patients for anti-HLA class I, 55.0% for anti-HLA class II, and 45.0% for anti-MICA. Histological findings were generally favorable. ICI scores were low, with 65.0% of samples scoring 0 and 35.0% scoring 1. A nominal positive correlation was observed between anti-HLA class I NBG ratio and ICI; however, this finding did not remain statistically significant after correction for multiple comparisons. Exploratory PBM subgroup estimates were directionally different but were based on very small subgroups and should not be interpreted as evidence of effect modification. (4) Conclusions: The findings suggest a possible hypothesis-generating link between baseline humoral sensitization and mild local inflammatory infiltrates, which requires validation in larger, prospectively powered studies with predefined histological and immunological endpoints. Full article

Background: Platinum-based chemotherapy, including cisplatin and carboplatin, is widely used to treat various cancers, including ovarian cancer. However, its clinical application is limited by dose-limiting toxicities and resistance, with a poor 5-year overall survival rate for ovarian cancer (35–40%). In this study, we used ionisable lipids and developed pH-responsive lipid nanoparticles (LNPs) to address platinum-resistance in ovarian carcinoma. Methods: Cisplatin was loaded into three LNP systems containing monoolein (MO) and synthetic cationic ionisable lipids (OE-Mo, OA-Py, and OA-Pi) dispersed in Pluronic F-127 with 0.9% NaCl. Cisplatin-loaded LNPs (Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP) were characterised for size, zeta potential, and internal mesophase structure. Encapsulation efficiencies were determined via HPLC after removing free drug by ultrafiltration. In vivo efficacy was tested using cisplatin-resistant human patient-derived xenograft (PDX) models. Results: The LNPs were well dispersed with particle size of 219–250 nm and a drug loading of ~1.2 mg/mL. Encapsulation efficiencies were 62%, 59%, and 64%, for Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP, respectively. Small angle X-ray scattering (SAXS) results showed that the LNPs are pH responsive with structural transitions from a cubic to a hexagonal phase at an acidic pH. Among the tested formulations, Cis-OA-Py-NP resulted in the most significant reduction in tumour volume by ~60% compared to treatment with cisplatin alone. However, they also showed significant toxicity, including >10% weight loss and gross lung and kidney damage, as confirmed by histology. Conclusions: These findings highlight the potential of Cis-OA-Py-NP in reducing tumour volume but underscore the need for further optimisation to improve safety and therapeutic applicability. Full article

Objectives: The dependence of non-small cell lung cancer (NSCLC) on glutamine has made targeting glutamine metabolism an attractive therapeutic approach. Dietary interventions are increasingly considered as adjuvant cancer therapies. This study aims to explore the relationship between glutamine starvation and ferroptosis in NSCLC and to elucidate the underlying molecular mechanisms. Methods: The effects of glutamine starvation were evaluated both in A549 and H460 NSCLC cell lines and in vivo using xenograft models in SCID mice. Assessments included cell viability, migration, clonogenic capacity, and the expression of key proteins. To gain mechanistic insight, AMPK was either overexpressed or inhibited, and key markers of ferritinophagy (including ULK1, BECN1, NCOA4, and LC3-II/I) and ferroptosis (such as ACSL4, GPX4, and xCT) were analyzed. Results: Glutamine starvation markedly suppressed tumor growth in both in vitro and in vivo settings, while also reducing cell migration and clonogenicity in cultured cells. This intervention activated AMPK, as indicated by increases in both total and phosphorylated forms, and upregulated PDZD8 expression. Mechanistically, AMPK activation played a critical role in driving ferritinophagy and ferroptosis—manipulation of AMPK consistently altered key markers of these processes. Furthermore, AMPK levels influenced PDZD8 protein expression. Notably, overexpressing PDZD8 alone was sufficient in promoting both ferritinophagy and ferroptosis, indicating that PDZD8 acts as a critical downstream mediator of AMPK in this pathway. Conclusions: Our findings reveal that glutamine starvation triggers ferroptosis in NSCLC via activation of ferritinophagy, mediated by the AMPK/PDZD8 signaling pathway. These results support the potential of dietary glutamine restriction as a novel therapeutic approach for NSCLC. Full article

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. Full article

Alveolar ridge preservation (ARP) aims to reduce post-extraction bone resorption and facilitate implant placement. Among alloplastic grafts, β-tricalcium phosphate (β-TCP) is widely used due to its osteoconductive properties and complete resorbability. This systematic review evaluated the clinical effectiveness of β-TCP for ARP, focusing on ridge dimensional changes assessed by cone–beam computed tomography (CBCT). Electronic searches were performed in major scientific databases up to April 2026. Randomized controlled trials (RCTs) reporting CBCT-based dimensional outcomes after at least 4 months were included. Five RCTs met the inclusion criteria. Considerable heterogeneity was observed in biomaterial formulations, socket management, and outcome assessment. When used alone, β-TCP showed variable results, ranging from greater ridge resorption compared with xenograft to outcomes comparable with those of freeze-dried bone allograft. More consistent findings were reported when β-TCP was used in combination with other biomaterials, with outcomes generally comparable to those of deproteinized bovine bone mineral (DBBM). Overall, β-TCP may have a potential role in alveolar ridge preservation; however, evidence remains limited and heterogeneous. Differences between β-TCP alone and composite formulations should be carefully considered, and no definitive conclusions can be drawn regarding its comparative predictability versus xenografts. Further RCTs are needed to clarify its clinical effectiveness and identify optimal applications. Full article

Antibody–drug conjugates (ADCs) are a promising therapeutic modality for treating cancer. TM4SF1 is an integral membrane protein that internalizes from the cell surface along microtubules to the nucleus and is highly expressed on the surface of both tumor endothelium and tumor cells. We previously reported that in human tumor xenografts in mice, an ADC directed to mouse TM4SF1 (2A7A-LP2) effectively regressed tumors through an anti-vascular mechanism, and an ADC directed to human TM4SF1 (v1.10-LP2) effectively regressed tumors through an anti-tumor cell mechanism. In this study, we investigated the actions of the mouse TM4SF1-directed ADC on VEGF-A-provoked angiogenic vessels. We employed an adenovirus expressing mouse VEGF-A¹⁶⁴ (Ad-VEGF-A) to induce surrogate tumor blood vessels in the ears of nude mice. We showed that an immune effector function-ablated ADC, 3m2A7A-LP2, was better tolerated than its parent 2A7A-LP2. Homing of 3m2A7A to Ad-VEGF-A-induced new blood vessels became evident within six hours after intraperitoneal injection. A single dose of 3m2A7A-LP2 at 3 mg/kg disrupted evolving Ad-VEGF-A-provoked blood vessels within forty-eight hours, and three doses of 3m2A7A-LP2 at 48 h intervals caused striking local ear necrosis; in each case, there was no apparent harm to vessels in the corresponding control virus-injected ears and the surrounding tissues of the same mice. Our studies demonstrate that an ADC-directed against mouse TM4SF1 specifically targeted the newly formed blood vessels induced by Ad-VEGF-A at multiple stages of their development. Thus, TM4SF1-directed ADCs, through their ability to target angiogenic vessels, represent an alternative anti-angiogenic approach for treating solid tumors. Full article

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by poor survival. Despite a high tumor mutation burden, biomarker discovery in SCLC remains challenging due to rapid tumor plasticity and limited tissue availability, highlighting the promise of liquid biopsy-based approaches. Epigenetic dysregulation of DNA 5-hydroxymethylcytosine (5hmC) has emerged as a cancer hallmark. However, its role in SCLC remains largely unexplored. Here, we characterized the cell-free DNA (cfDNA) 5hmC landscape in SCLC and evaluated its potential applications. We profiled the cell-free hydroxymethylomes of 107 pre-treatment SCLC patients and 53 matched controls using the 5hmC selective chemical labeling (5hmC-Seal) assay. SCLC displayed higher global 5hmC levels and distinct enrichment at neurodevelopmental and synaptic pathways, consistent with the neuroendocrine identity of SCLC. Concordance between plasma and matched circulating tumor cell patient-derived xenograft (CDX) demonstrated that cfDNA 5hmC reflects tumor epigenetic states and correlates with transcriptomic-derived molecular subtypes. Elevated SCLC-specific 5hmC levels and extensive stage (ES) disease were associated with inferior survival, with ES disease showing enrichment of pathways linked to cellular plasticity and neurodevelopment. Together, these findings indicate that cfDNA 5hmC profiling has potential as a biologically informative and clinically relevant biomarker in SCLC, with possible applications in tumor subtyping and risk stratification. Full article

Background/Objectives: While ¹⁷⁷Lu-DOTATATE has demonstrated clinical efficacy in peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs), current dosing regimens do not account for potential sex-based pharmacokinetic differences. Our study systematically characterizes sex-dependent pharmacokinetic variations of ¹⁷⁷Lu-DOTATATE in preclinical models to provide the first preclinical evidence base informing future sex-stratified clinical investigations. Methods: Sex-stratified pharmacokinetic and biodistribution studies were conducted in male and female SD rats following intravenous administration of ¹⁷⁷Lu-DOTATATE at multiple dose levels: 2.86, 5.71, and 11.43 mCi/kg. Metabolic stability and renal excretion patterns were characterized. Safety assessments included acute toxicity, vascular irritation, hemolysis, and allergenicity testing. Therapeutic efficacy was evaluated exclusively in female AR42J xenograft-bearing CB-17 SCID mice. Results: Significant sex-dependent pharmacokinetic differences were observed at high (11.43 mCi/kg) and low (2.86 mCi/kg) dose levels, with females exhibiting 30–40% higher AUC and C_max values compared to males (p < 0.05). Both sexes demonstrated preferential accumulation in SSTR-expressing tissues, particularly the pancreas (females: 10.87 ± 2.51% ID/g; males: 9.10 ± 0.76% ID/g) and adrenal glands, with rapid clearance from non-target organs. Radio-HPLC analysis confirmed high metabolic stability with no detectable radiolabeled metabolites, and over 90% of radioactivity was recovered through renal excretion. Safety assessments demonstrated excellent tolerability across dose levels. In female xenograft models, treatment achieved tumor growth inhibition of 92.35–96.44% and 100% survival rate versus 10% in controls, though mid/high doses caused weight loss. Conclusions: Our study provides systematic preclinical evidence of sex-dependent pharmacokinetic differences in ¹⁷⁷Lu-DOTATATE, with females demonstrating significantly higher systemic exposure than males at specific dose levels. These findings establish the systematic preclinical evidence base for sex-dependent pharmacokinetic differences in ¹⁷⁷Lu-DOTATATE, providing a scientific rationale for incorporating sex as a stratification variable in future dosimetry-guided clinical studies. Full article

Cervical cancer constitutes a major global health burden with a high incidence rate. Despite its well-established role in genome stability and cell cycle regulation, its specific anti-tumor mechanism involving the induction of a senescence-like state remains unclear. To determine whether Mg²⁺ impedes cervical cancer progression through the induction of a senescence-like phenotype via the ATM/CHK2/p21 pathway, HeLa cells were used in this study. Cell proliferation, migration, and invasion were measured using CCK-8, EdU, wound-healing, and Transwell assays, while SA-β-gal staining and western blotting served to examine both senescence-related markers and pathway protein expression. A BALB/c nude mouse xenograft model was established to evaluate tumor growth and safety following intratumoral Mg²⁺ injection. The results showed that Mg²⁺ inhibited proliferation, migration, and invasion in a concentration-dependent manner. Treatment with 20 mM Mg²⁺ increased SA-β-gal positivity, decreased Lamin B1 expression, and activated the ATM/CHK2/p21 pathway; moreover, this upregulation of p21 was reversed by an ATM inhibitor. ELISA revealed that 10 mM Mg²⁺ enhanced IL-6 and TNF-α secretion, confirming effective induction of the senescence-associated secretory phenotype, while higher concentrations diminished this effect, which may be partly attributed to the reduction in cell viability. In vivo experiments showed that Mg²⁺ inhibited tumor growth without notable alterations in body weight, liver and kidney function, or serum magnesium levels. In summary, the localized high concentration of magnesium ions induces cells to enter a senescence-like state via the ATM/CHK2/p21 pathway, thereby selectively suppressing malignant cellular behaviors. Notably, its in vivo efficacy and safety profile in vivo are favorable. It is also worth noting that these findings should be interpreted within the context of a preclinical, high-dose local Mg²⁺ model. Full article

Background: To investigate whether coating xenogeneic bone grafts with hyaluronic acid influences early osteogenic and fibrotic marker expression in vitro. Methods: Three xenograft materials were evaluated, including one hyaluronic acid-coated product and two uncoated deproteinized bovine bone mineral products, all commercially available. Human osteoblast-like cells (U2OS) and bone marrow stromal cells (HS5) were cultured with material extracts. Proliferation was assessed using XTT assay at 24 and 48 h. Cell adhesion was evaluated through fluorescence microscopy. Osteogenic markers (RUNX2, COL1A1) and fibrotic markers (COL3A1, TGF-β3) were quantified using quantitative real-time PCR. Statistical analysis employed one-way ANOVA with Benjamini–Krieger–Yekutieli (BKY) two-stage FDR correction for datasets that met the normality assumption, and the Kruskal–Wallis test with Dunn’s post hoc test for non-normally distributed data (HS5 XTT assay). Pairwise comparisons were restricted to each xenograft group versus the untreated control; an adjusted p-value < 0.05 was considered statistically significant. Results: At 48 h, the HA-coated xenograft (Xeno1) showed the highest mean metabolic activity in U2OS cells (0.538 ± 0.056) compared with the uncoated Xeno2 (0.450 ± 0.120) and Xeno3 (0.439 ± 0.073); however, after FDR correction no statistically significant differences were observed between groups. The coated material was associated with upregulation of early osteogenic markers, 2.61-fold RUNX2 upregulation (p = 0.01) compared to untreated cells. Both coated and uncoated xenografts demonstrated equivalent suppression of fibrotic markers in HS5 cells, reducing COL3A1 by 92.7% (p = 0.001) and TGF-β3 by 92.1% (p = 0.001). Conclusions: These exploratory in vitro findings suggest that HA coating may enhance early osteogenic marker expression. The observed effects on stromal markers warrant further investigation using primary cells, additional fibrotic endpoints (e.g., TGF-β1, ACTA2), and in vivo models before translational conclusions can be drawn. Full article

Objective: Effectively eliminating xenoimmunogenicity and achieving recellularization in cardiac xenografts remains a critical challenge in developing an ideal implantable xenograft. We have previously demonstrated that the removal of major antigens, including Galα1-3Gal (α-Gal) epitope and non-human sialic acid N-glycolylneuraminic acid (Neu5Gc), using α-galactosidase and peptide N-glycosidase F (PNGase-F), enables a synergistic effect with decellularization, significantly reducing the expression of carbohydrate-binding lectins without altering the biomechanical properties of the graft. The aim of this study was to establish an effective method for in vitro recellularization by seeding human mesenchymal stem cells (MSCs) on decellularized cardiac xenografts that had undergone optimal xenoantigen removal using α-galactosidase and PNGase-F. Additionally, this study aimed to evaluate the potential for in vivo recellularization. Methods: Decellularized porcine pericardium scaffolds treated with both enzymes were further modified by forming a fibrin mesh on their surface and within their structure, followed by the attachment of heparin and human vascular endothelial growth factor to the mesh. Subsequently, the scaffolds were seeded with human adipose tissue-derived stem cells for 8 weeks. In vitro recellularization, differentiation, and extracellular matrix remodeling of decellularized and enzyme-treated xenografts were assessed using vimentin, calponin, fibronectin, CD31, VWF, and phalloidin staining. To evaluate the potential for in vivo recellularization, decellularized glutaraldehyde-crosslinked xenografts with anticalcification treatments were seeded with rat bone marrow MSCs and implanted into rats subcutaneously to evaluate cell infiltration and calcification via histology, von Kossa staining, and micro-computed tomography. Results: In decellularized xenografts treated with both enzymes, stronger signals were detected and mesenchymal cell infiltration into the tissue was significantly faster, leading to accelerated recellularization. This recellularization process was more pronounced as time went on, with greater cell infiltration and evidence of cell differentiation. An in vivo study showed that decellularization and anticalcification treatments revealed stronger vimentin staining in histological analysis. The recellularization for our biocompatible scaffolds exhibited a lower degree of calcification compared to the non-recellularized tissue. Conclusions: We successfully developed major xenoantigen-free scaffolds by demonstrating the safety and synergistic effect of α-galactosidase and PNGase-F treatments and proved, for the first time, the effectiveness of recellularization using a human MSC monoculture on xenoantigen-free scaffolds. Furthermore, there was potential for in vivo recellularization of our biocompatible scaffolds seeded with MSCs. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality worldwide, primarily due to the systemic toxicity and drug resistance associated with conventional doxorubicin (DOX) therapy. To overcome these limitations, we developed and optimized a novel cationic-ionizable lipid nanoparticle platform, QTPlus, for the co-delivery of DOX and siRNA targeting fibroblast growth factor 2 (siFGF2). Methods: The study evaluated the physicochemical properties, cellular uptake, gene regulation, apoptosis induction, and in vivo antitumor efficacy and safety of QTPlus-DOX-siFGF2 in breast cancer models. Results: QTPlus nanoparticles based on the A-066 formulation achieved uniform particle size (~218 nm), low polydispersity (PDI 0.164–0.214), and high encapsulation efficiencies (DOX: 49.56 ± 0.15%; siFGF2: 77.66 ± 1.30%). In vitro release studies revealed a robust pH-responsive profile, characterized by sustained stability at physiological pH (7.4) and rapid burst release at acidic endosomal pH (5.5). In MCF-7 and MDA-MB-231 cells, QTPlus-DOX-siFGF2 significantly enhanced cellular uptake, downregulated FGF2 (0.639-fold) and VIM (0.373-fold), and upregulated CASP3 (3.364-fold in siFGF2 group) and BRCA1 (4.041-fold). Flow cytometry showed markedly increased apoptosis (78.5% vs. 42.65% for QTPlus-DOX alone). In the MDA-MB-231 xenograft model, QTPlus-DOX-siFGF2 achieved 65.87% tumor growth inhibition with stable body weights and favorable trends in cardiotoxic biomarkers. Conclusions: These results demonstrate that QTPlus enables effective co-delivery of DOX and siFGF2, producing synergistic antitumor effects through apoptosis induction and suppression of epithelial–mesenchymal transition while improving the safety profile. QTPlus-DOX-siFGF2 represents a promising nanotherapeutic strategy for breast cancer warranting further clinical development. Full article