Self-assembled nanoparticles overcoming hypoxic and acidic microenvironment to synergistically potentiate ferroptosis in triple-negative breast cancer.

Ferroptosis-sensitizing nanoprodrug system for synergistic therapy of triple-negative breast cancer.

Glutathione- responsive Phototheranostic platform for imaging-guided enhanced oxidation photoimmunotherapy-ferroptosis synergistic hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide, with a five-year survival rate of only 19%. Although Sorafenib is the primary systemic therapy, its limited efficacy and complex interactions with signaling pathways highlight the need for multi-target drugs. This study evaluates the anti-cancer properties of selected phytochemicals against six key HCC target proteins, utilizing sorafenib tosylate as a positive control. Molecular docking was performed to evaluate binding affinities and interactions, and ADME/T predictions were generated to estimate drug-like properties. The top-ranking candidates were further evaluated using 100-ns molecular dynamics simulations to analyze conformational stability, protein-ligand interactions, and residue mobility. Silymarin (SA) emerged as the most effective compound, demonstrating greater predicted inhibitory activity than Sorafenib. SA showed high binding affinity for target proteins 6HH1 (-9.9 kcal/mol) and 1CM8 (-9.6 kcal/mol). Molecular dynamics simulations also revealed increased stability of the SA-protein complexes, particularly for the 1CM8-SA complex, which maintained high conformational stability. The root-mean-square deviation (RMSD) value was found to be around 2.1 Å, and the root-mean-square fluctuation (RMSF) values were below 3 Å, indicating lower protein flexibility compared to both the native and sorafenib-bound complexes. These computational findings provide a strong theoretical basis for Silymarin's efficacy as a highly potent, multi-targeted therapeutic agent against HCC. The improved stability and binding properties of Silymarin compared with Sorafenib provide a strong rationale for advancing this compound into preclinical and clinical studies.

This study aimed to identify novel key targets and mechanisms for repurposing strategies and mitigating sorafenib (SFB) resistance using the GEO transcriptomic dataset GSE94550 within a systems pharmacology framework. Potential counteracting molecules against SFB were retrieved from chemical repositories, followed by molecular docking tests (MDT), Kaplan–Meier survival analysis, and density functional theory (DFT) assessments to evaluate therapeutic potential. PPI networks were constructed using STRING and R to characterize the relationships between upregulated and downregulated genes. The most relevant signalling pathways associated with major targets were determined to elucidate the upstream regulatory mechanisms. Among the differentially expressed genes, APOB emerged as a pivotal regulator (log2FC ≥ +2 or ≤ −2), modulating fifteen genes, including eleven upregulated and four downregulated nodes. At stricter thresholds (log2FC ≥ +3 or ≤ −3 and ≥ +4 or ≤ −4), CD44 was identified as a key upregulated target. Its inhibition – particularly by verbacoside – was strongly associated with suppression of the ECM–receptor interaction pathway, suggesting a significant therapeutic axis. This study illuminates the molecular landscape of SFB-resistant environments through an integrative network approach and highlights verbacoside as a promising agent capable of attenuating SFB resistance, supporting its potential role in combination therapy.

Liver cancer remains a major global health challenge, with limited therapeutic options for advanced stages. Sorafenib, the standard first-line systemic therapy, provides only modest survival benefits and is frequently associated with drug resistance and adverse effects, necessitating the exploration of safer and more effective combination therapies. Frankincense, the olibanum gum resin from Boswellia sacra Flück.(Burseraceae), has long been used as a traditional medicinal remedy and is known to target multiple biological pathways, with diverse therapeutic activities. Owing to its reported multi-target anticancer, anti-inflammatory, and pro-apoptotic properties, frankincense represents a promising candidate for combination therapy aimed at enhancing sorafenib efficacy while potentially reducing required doses and associated toxicity. This study aimed to evaluate the cytotoxic activity of frankincense aqueous extract (FrAE) alone and in combination with sorafenib (SOR) against the hepatoblastoma cell line HepG2. Phytochemical analysis tentatively identified five diterpenoids and sixteen triterpenoids in FrAE. Both FrAE and SOR exhibited dose-dependent cytotoxicity, and their combination selectively enhanced cytotoxic effects, reducing the effective concentration of SOR and demonstrating strong synergism (CI = 0.298). Mechanistically, the combination induced integrated anticancer effects characterized by enhanced apoptosis and necrosis, activation of autophagic signaling, and marked inhibition of HepG2 cell migration, accompanied by cell cycle disruption across multiple phases. Molecular docking further supported these findings by demonstrating favorable binding of FrAE-derived terpenoids to key apoptotic (BCL-2, p53) and autophagic (mTOR, LC3C) regulators. Collectively, these findings suggest that the aqueous extract of frankincense enhances the anticancer efficacy of sorafenib, representing a promising adjuvant strategy for the management of liver cancer.

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis (Mtb). Emergence of drug resistance in Mtb requires continuous enrichment of anti-tubercular medication. Inclusion of host-directed therapies holds considerable promise in this context. Sorafenib (SRB) is a multi-kinase inhibitor targeting VEGF receptor kinase, Raf, MEK, and extracellular signal-regulated kinase (ERK) signaling cascade to treat several types of cancer, including hepatocellular carcinoma. We have previously established that SRB allosterically inhibits ornithine acetyltransferase (MtArgJ), an essential enzyme in the arginine biosynthesis pathway of Mtb, thereby limiting bacterial growth in culture at a minimum inhibitory concentration of 10 µg/mL. The current work focuses on how SRB at the dose of 30 mg/kg body wt inhibits the pathogenicity and survival of bacteria in a preclinical mouse model of tuberculosis by inducing pro-apoptotic and immunomodulatory mechanisms in the host. We observed that SRB treatment promotes apoptosis in Mtb-infected and -uninfected THP-1 cells, human monocyte-derived macrophages. Concomitantly, SRB treatment reduces infection-associated necrosis in the Mtb-infected THP-1 cells. We further noted the upregulated expression of pro-apoptotic proteins during SRB treatment in preclinical mouse models. In addition, we investigated the expression of pro- and anti-inflammatory cytokines and immunomodulation in lung tissues treated with SRB. Interestingly, SRB treatment increased the number of arginase 1-positive macrophages, which are reckoned to enhance tissue healing. In conclusion, our research discloses that SRB is helpful in both lowering the tubercular burden and accelerating recovery of damaged tissue by harnessing the host immune response.IMPORTANCEHost-directed therapies hold considerable promise for treating drug-resistant Mycobacterium tuberculosis (Mtb). In this context, the induction of apoptotic and immunomodulatory responses in the host by sorafenib (SRB) is demonstrated here to compromise the survival and pathogenic potential of Mtb in a preclinical mouse model of TB and in Mtb-infected and -uninfected THP-1 cells. Concurrently, the infection-associated necrosis in the Mtb-infected THP-1 cells is also reduced. Furthermore, arginase 1-positive macrophages, which are known to enhance tissue healing, are increased in SRB-treated groups. Thus, SRB treatment not only lowers the tubercular load but also aids in healing damaged tissues by leveraging the host immunity.

Hepatocellular carcinoma (HCC) is one of the significant threats to human health worldwide, and its conventional treatments have obvious limitations. With the development of nanomedicine, the strategy of integrating multiple therapeutic approaches into a single nanoplatform is expected to lead to more efficient treatment of tumors. This study utilizes the nanomaterial PCN-224 as a carrier, labels it with 177 Lu, and modifies its surface with sorafenib (SOR) to construct an integrated diagnostic and therapeutic nanoplatform. The surface modification of SOR not only functions as targeted therapy (TT), but also enhances the active targeting of the nanoparticles and their accumulation at the tumor site. This in vivo distribution could be monitored by dual-modality imaging using fluorescence imaging and SPECT/CT imaging. The long retention allows 177 Lu-mediated radioisotope therapy (RIT) to continue working inside the tumor, thereby improving the limitations of photodynamic therapy (PDT), where the depth of light penetration is limited. Additionally, all three therapeutic modalities can act as inducers of immunogenic cell death (ICD), thereby further enhancing the therapeutic effects by activating the immune response. In conclusion, this work designs a combined triple therapy of PDT-RIT-TT to treat HCC through the direct killing effect and the indirect effect of ICD, utilizing multiple synergistic effects to improve the shortcomings of single therapy, and shows promising prospects for clinical application. • Design of modified sorafenib to modify the surface of nanoparticles to enhance their active targeting capability • Triple synergistic induction of immunogenic cell death by the combination of PDT-RIT-TT • Dual-modality imaging of fluorescence imaging and SPECT/CT imaging synergistically monitors the in vivo distribution of nanoparticles

Solid tumors present formidable barriers to immunotherapy due to low immunogenicity and a highly suppressive microenvironment. This study introduces Hb-DD@SRF, a mutually reinforcing nanoplatform comprising a sorafenib (SRF)-loaded core coated with a dual-targeting hemoglobin (Hb) shell. Upon targeting iron transporters on tumor cells, Fe2+ derived from Hb catalyzes reactive oxygen species (ROS) generation, while acidic conditions trigger SRF release to inhibit glutathione peroxidase 4 (GPX4), synergistically amplifying ferroptosis. This robust process elicits immunogenic cell death to prime T cells. Crucially, Hb-mediated oxygenation precisely offsets the severe hypoxia resulting from SRF, establishing a complementary loop that prevents drug resistance. Furthermore, the platform targets M2 macrophages via the haptoglobin pathway, where oxygen and SRF jointly reprogram them to reverse immunosuppression. This remodeled immunostimulatory microenvironment synergizes with anti-PD-L1 therapy to achieve pronounced suppression of primary and metastatic tumors. Collectively, Hb-DD@SRF orchestrates ferroptosis amplification and comprehensive microenvironment modulation to potentiate antitumor immunotherapy.

Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.

Ashwagandha (W. somnifera), known for its broad health benefits, has shown potential in cancer prevention and treatment. The aim of this study was to investigate the potential effect of ashwagandha aqueous extract (ASH-AE) on cell proliferation and therapy resistance markers in hepatocellular carcinoma (HCC). An in vitro study was conducted using the HepG2 cell line. The HepG2 cells were divided into 4 groups according to the treatment regimen received. ASH-AE was extracted from the whole plant and characterized by GC-MS and HPLC. HepG2 cell viability was determined for all groups. The protein expression of cluster of differentiation 90 (CD90) was determined by flow cytometry technique. Also, the gene expression of Sonic Hedgehog (SHH), Patched 1(PTCH1) and ATP-binding cassette subfamily C1 (ABCC1) was assayed by qRT-PCR. The protein expression and localization of glioma-associated oncogene 1 (Gli1) in HepG2 cells were determined by immunocytochemistry (ICC) assay. The results indicated that ASH-AE either alone or in combination with sorafenib (SOR) significantly reduced HepG2 cell viability in a concentration dependent manner (P ˂0.001) with IC50 was 6.65mg/ml for ASH-AE, 11.3 µM for SOR, and 5.6mg/ml + 18.6 µM for ASH-AE in combination with SOR. Moreover, SOR significantly increased the percentage of CD90+ cells and Gli1 protein expression and nuclear translocation as well as ABCC1 gene expression compared to untreated cells. On the other hand, ASH-AE either alone or in combination with SOR significantly decreased the percentage of CD90+ cells and Gli1 expression and nuclear translocation as well as SHH, PTCH1 and ABCC1 gene expression compared to untreated cells and that treated with SOR. We concluded for the first time that the combination of SOR and ASH-AE generates antagonistic antitumor effect in HepG2 cells. Moreover, ASH-AE can inhibit proliferation of HepG2 cells and mitigate sorafenib-induced resistance-associated markers in HepG2 cells by targeting CD90+ cells via Hedgehog pathway modulation.

Sorafenib (SOR)/simvastatin (SIM) dual-drug self-assembled nanoparticles for synergistic induction of tumor ferroptosis.

Portal vein tumor thrombus (PVTT) is a common and severe indicator in advanced hepatocellular carcinoma (HCC), characterized by a poor prognosis and limited response to existing therapies. Cancer-associated fibroblasts (CAFs) play an important role in promoting HCC metastasis and contribute to resistance against sorafenib (SOR) resistance, which is a standard treatment for advanced HCC. The data from single-cell RNA sequencing highlights the critical role of C-X-C motif chemokine ligand 12 (CXCL12) in the activation of CAFs. To address these challenges, we develop a PVTT-targeted nanocarrier designed to co-deliver small interfering RNA (siRNA) and a multikinase inhibitor, aiming to enhance therapeutic outcomes for PVTT. This novel lipid-coated polylactide-co-glycolide nanoparticle system effectively downregulate CXCL12 expression in CAFs, leading to their inactivation and subsequent reshaping of the tumor microenvironment. The resulting modulation of the tumor microenvironment significantly suppress tumor cell migration, invasion, and resistance to SOR, thereby demonstrating potent anti-tumor effects in orthotopic mouse models of PVTT. Furthermore, RNA sequencing reveals key regulatory pathways and genes associated with the inhibition of SOR resistance and PVTT formation mediated by these nanoparticles. These findings suggest that modulating the tumor microenvironment, combined with targeted anti-tumor therapies, offers a promising strategy for treating HCC patients with PVTT.

Atezolizumab plus bevacizumab (Atez/Bev) has become the standard first-line therapy for advanced hepatocellular carcinoma (HCC), but optimal second-line strategies remain unclear. This multicenter retrospective study compared survival outcomes and tumor control among first-line regimens and evaluated post-progression efficacy. We retrospectively analyzed 1542 patients with advanced HCC who received sorafenib (SOR), lenvatinib (LEN), or Atez/Bev between 2009 and 2022. The main cohort (n = 612) excluded patients who underwent concomitant or inter-line locoregional therapy or entered clinical trials after first-line treatment. Overall survival (OS), progression-free survival (PFS), post-progression survival (PPS), duration of disease control (DDC), and duration of response (DOR) were estimated by Kaplan-Meier analysis and compared by the log-rank test. The impact of disease control and objective response on OS was assessed using time-dependent Cox models. Median OS was 15.4 months for SOR, 13.1 for LEN, and 20.6 for Atez/Bev (p = 0.002); Median PFS was 3.5, 5.7, and 7.5 months, respectively (p < 0.001); and median PPS was 10.8, 6.4, and 9.0 months, respectively (p = 0.049). Atez/Bev achieved the longest DDC (8.5 months) and DOR (22.1 months). Disease control and objective response were associated with improved OS (HR: 0.51/0.42 for SOR, 0.54/0.62 for LEN, 0.34/0.35 for Atez/Bev). After progression, median second-line PFS was 5.5 months for SOR, 2.5 for LEN, and 3.0 for Atez/Bev (p = 0.001). Atez/Bev provided superior survival and durable tumor control; however, post-progression outcomes remained unsatisfactory, underscoring the need for improved second-line approaches after Atez/Bev failure.

Hepatocellular carcinoma (HCC), accounting for 75-85% of liver cancers, faces limited therapeutic efficacy due to late-stage diagnosis, high malignancy, and poor drug permeability. Sorafenib (SF), a first-line multi-kinase inhibitor for unresectable HCC, suffers from low tumor-targeting efficiency and adverse effects. This study proposes a urease-driven nanomotor system(CUNMs + SF) to enhance SF delivery and tumor penetration. The nanomotors utilize porous magnetic silica nanoparticles(PMSNs) loaded with SF and modified with cyclodextrin-urease hybrids. This design enables magnetic targeting to HCC sites and autonomous propulsion via urea-fueled enzymatic conversion, overcoming physiological barriers in the tumor microenvironment.The system exhibits pH-responsive drug release (triggered at pH < 6.5) and induces ferroptosis in HCC cells by inhibiting the SLC7A13/GSH/GPX4 pathway, effectively suppressing tumor growth. In vitro and in vivo experiments demonstrate superior tumor accumulation, deep tissue penetration, and enhanced therapeutic outcomes compared to conventional SF. This work pioneers the application of enzyme-powered nanomotors in HCC therapy, addressing the limitations of systemic drug delivery while leveraging tumor-specific biochemical cues. The findings highlight the potential of biohybrid nanomotors for targeted cancer treatment and inspire future developments in stimuli-responsive nanomedicine for challenging malignancies.

Abstract Sorafenib Tosylate (ST), a kinase inhibitor, is an anti-cancer agent that prevents abnormal proteins from signaling cancer cells to proliferate. Novel Fourier Transform Infra-Red (FTIR) and Raman spectroscopies, covering 200–4000 cm −1 , were analyzed to understand the dynamics of this molecule. Numerous peaks in the FTIR and Raman spectra were assigned based on Density Functional Theory (DFT) calculations with three types of basis sets: 3–21G, 6−31G(d), and 6−31+G(d,p). The scale factor of 0.94955, closest to the ideal value of 1.0 for 3–21G, was determined by excluding intramolecular hydrogen-bond frequencies from our limited dataset. We accurately assigned the IR and Raman bands to the ST molecule by corroborating the recorded spectra with calculated DFT spectra. The findings of this study can provide valuable insights into current research on cancer treatment with kinase inhibitors.

Chemotherapy resistance continues to represent a profound impediment in oncologic therapy, and the co-delivery of chemotherapeutic agents with distinct mechanisms of action offers an effective approach. In the present investigation, we developed Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Sorafenib (SOR), a ferroptosis inducer, and Venetoclax (VTX), an apoptosis inducer for combined cell death. These PLGA(SOR + VTX) NPs were formulated via nanoprecipitation followed by successive coating with polydopamine (PDA) and bovine serum albumin (BSA). PDA was utilized to facilitate BSA linkage while BSA enabled targeting of albondin and secreted protein acidic and rich in cysteine (SPARC) receptors. BSA-PDA-PLGA(SOR + VTX) NPs revealed a spherical morphology with a size of 183.6 ± 6.20nm, a PDI of 0.108 ± 0.02, and a Z-potential of -23.3 ± 1.03mV with SOR and VTX ratiometrically (1:1) loaded into the nanoparticles. The nanoparticles exhibited sustained release behaviour and were assessed to be hemocompatible. The cell uptake studies reflected better cytoplasmic internalization, and the formulation resulted in a reduction in the IC50 value by 2.74, 3.40, and 2.90-fold compared to the physical combination of SOR + VTX in MDA-MB-231, A549, and HeLa cell lines, respectively. The apoptosis index of the formulation was 1.42, 1.40 and 1.40-fold higher than that of SOR + VTX in MDA-MB-231, A549 and HeLa, respectively. Moreover, BSA-PDA-PLGA(SOR + VTX) NPs induced a greater generation of reactive oxygen species and mitochondrial membrane potential depolarization. They also demonstrated escalated ferroptosis by depleting glutathione and elevating malondialdehyde levels across all cell lines. Thus, co-delivery of SOR and VTX via BSA-PDA-PLGA NP exhibited synergistic activity in targeting different tumor cells.

Clinical tumor management is hindered by insufficient therapeutic efficacy and systemic side effects. Ferroptosis and cuproptosis, emerging metal ion-disruption-driven regulated cell death pathways, hold significant therapeutic potential. However, their combined efficacy is constrained by the tumor microenvironment (TME), where elevated levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4) effectively mitigate reactive oxygen species (ROS) and lipid peroxidation. To overcome these barriers, we developed a biomimetic Cu-MOF-sorafenib nanoassembler (CMSP) for synergistic cuproptosis-ferroptosis-based anticancer therapy. CMSP comprises sorafenib (SOF)-loaded Cu-MOFs coated with tumor cell lysate–derived proteins. It exerts robust antitumor effects through three interconnected mechanisms: i) The tumor lysate coating facilitates homotypic targeting and immune evasion, thereby enhancing tumor-specific accumulation; ii) The acidic TME triggers the release of copper ions, which amplify ROS generation via Fenton-like reactions, while SOF inhibits System Xc−, thereby depleting GSH and downregulating GPX4 expression; iii) Copper ions induce the aggregation of lipoylated proteins, initiating cuproptosis, while SOF synergistically promotes lipid peroxidation, driving ferroptosis. Both in vitro and in vivo studies demonstrate the efficient tumor accumulation, growth suppression, and metastasis inhibition of CMSP. By integrating biomimetic targeting, oxidative stress amplification, and dual-pathway synergy, CMSP presents a promising strategy to advance the development of personalized antitumor nanomedicines.

BackgroundIschemic stroke is a leading cause of morbidity and mortality worldwide, yet available therapeutic strategies remain limited. La ribonucleoprotein domain family member 7 (LARP7), a critical regulator of RNA stability and transcriptional control, participates in cellular stress responses and inflammatory modulation. Emerging evidence suggests LARP7’s involvement in neuroinflammation and neuronal survival, yet its role in ischemic stroke pathogenesis is still poorly understood.MethodsWe systematically investigated LARP7 expression in patients with acute ischemic stroke (AIS), mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), and neurons exposed to oxygen–glucose deprivation/reoxygenation (OGD/R). To elucidate the role of LARP7 in ischemic stroke, we generated neuron-specific LARP7 knockout mice, and employed a lentiviral delivery system for neuronal LARP7 overexpression. Protein interactions between LARP7-Sirt1 and Sirt1-NLRP3 were assessed using co-immunoprecipitation, proximity ligation assay, domain deletion analysis, and acetyl-proteomics. Furthermore, a potential LARP7 activator was identified through virtual screening, and its activation efficacy and neuroprotective effects were evaluated.ResultsLARP7 was markedly downregulated in the ischemic brain tissues from AIS patients and MCAO/R mice, as well as in OGD/R neurons. Neuronal LARP7 deficiency exacerbated neuronal pyroptosis and neurological deficits following ischemic stroke, which could be partially rescued by pharmacological activation of Sirt1. Mechanistically, LARP7’s C-terminal domain interacted with the N-terminal domain of Sirt1 to enhance Sirt1 deacetylase activity, which facilitated NLRP3 deacetylation at K21/K22/K24, thereby inhibiting inflammasome assembly and subsequent neuronal pyroptosis. Furthermore, sorafenib tosylate was identified as a potential LARP7 activator with demonstrated neuroprotective effects.ConclusionLARP7 enhances Sirt1 deacetylase activity to regulate NLRP3 deacetylation, thereby inhibiting inflammasome assembly and neuronal pyroptosis after ischemic stroke. Targeting LARP7 could represent a promising therapeutic strategy for ischemic stroke.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12974-025-03649-3.

This study investigates the interrelationships among drug loading, steric hindrance (Sh), defined as the spatial constraints imposed by the crystallized polymer network that physically restrict drug crystal growth, effective glass transition temperature (Tgᴱ), and drug particle size in crystalline solid dispersion (CSD) systems. Furthermore, we examine how CSD formulations enhance dissolution rates, oral bioavailability, and anti-liver cancer efficacy through comprehensive in vitro and in vivo studies. SOR-P188-CSD with different drug loadings were synthesized via spray drying, utilizing Sorafenib (SOR) as the model drug and poloxamer 188 (P188) as the carrier. The association between Sh/TgE, drug particle size, and dissolution behavior of CSDs was investigated by probing the crystalline domain (particle size), crystallization kinetics, and interaction dynamics within the CSD matrices. Notably, the particle size of SOR within SOR-P188-CSD exhibited a significant reduction compared to the pure drug. Analysis of crystallization kinetics unveiled a two-step crystallization mechanism for SOR-P188-CSD, where P188 crystallization preceded that of SOR. Intriguingly, an intermolecular interaction between SOR and P188 was observed, exerting an inhibitory effect on the crystallization kinetics of both components. This inhibitory effect escalated concomitantly with increasing drug loading. Within the SOR-P188-CSD system, P188 within formulations featuring low drug loading orchestrated a reduction in drug particle size by modulating the transverse and longitudinal growth rates of SOR, with Sh serving as the primary influencing factor. Conversely, in formulations with high drug loading, TgE of CSD interacted with temperature to regulate crystal nucleation and growth rates, thereby reducing drug particle size, with TgE emerging as the principal influencing factor. Subsequent in vitro and in vivo dissolution studies demonstrated a marked enhancement in the dissolution rate and bioavailability of drugs encapsulated within SOR-P188-CSD formulations compared to the active pharmaceutical ingredient (API). In the nude mouse liver cancer xenograft model, SOR-P188-CSD can significantly inhibit tumor growth by suppressing the expression of angiogenesis related factors (CD31, CD34, VEGF), tumor proliferation related factors (Ki67), and iron death related protein (GPX4). Collectively, our findings underscore the pivotal role of Sh/TgE in modulating drug particle size within CSD matrices through distinct mechanisms. Furthermore, our study underscores the potential of P188-mediated CSD formulations in augmenting the dissolution rate and bioavailability of poorly soluble drugs by minimizing drug particle size and sustaining drug supersaturation, thereby enhancing the efficacy of sorafenib in treating liver cancer.