Efficient Nanomedicine Research Articles

The Role of Artificial Intelligence and Machine Learning in Accelerating the Discovery and Development of Nanomedicine.

The unique potential of nanomedicine to address challenging health issues is rapidly advancing the field, leading to the generation of more effective products. However, these complex systems often pose several challenges with respect to their design for specific functionality, scalablemanufacturing, characterization, quality control, and clinical translation. In this regard, the application of artificial intelligence (AI) and machine learning (ML) approaches can enable faster and more accurate data assessment, identifying trends and predicting outcomes, leading to efficient nanomedicine product development. This perspective paper discusses the potential of AI and ML in nanomedicine product development with a focus on their applications in discovery, assessment, manufacturing, and clinical trials.The potential limitations of AI and ML approaches in nanomedicine product development are also covered.

Bi-modal confirmation of liposome delivery to the brain after focused ultrasound-induced blood-brain barrier opening

Focused ultrasound-mediated opening of the blood-brain barrier offers a great opportunity to deliver therapeutics into hard-to-treat brain tumors such as glioblastoma multiforme or diffuse midline glioma. However, the potential of the technique to offer a time window for efficient nanomedicine delivery has not been thoroughly studied. Non-invasive and targeted delivery of large drug-loaded nanocarriers, such as liposomes, could offer a safe and scalable method of personalized therapy for the treatment of brain pathologies. Additionally, it is essential to monitor the safety and efficacy of such treatments, tracking drug delivery in real-time through quantitative medical imaging.In this study, liposomes were modified to have an MRI contrast agent (i.e., Gd) in both lipid membrane and core, while an infrared dye (i.e., CW800) was coupled to lipids introduced in the lipid bilayer for bimodal detection and treatment verification. Targeted delivery of 110nm-in-diameter liposomes to the brain was quantified using 9.4-T MRI and near infrared fluorescence imaging. The spatiotemporal distribution of liposomes in vivo was assessed up to 4 hours post treatment using T1 weighted MRI. In vivo MRI signal co-localized with NIRF signal from excised brains ex vivo. Passive acoustic detection during treatments revealed a correlation between acoustic signal and MRI contrast, providing a scalable metric for assessing clinical treatment efficacy in real-time. In conclusion, therapeutic ultrasound exposure can enhance delivery of large trackable nanoparticles into the brain, while enabling real-time treatment monitoring and verification.

Predicting tissue distribution and tumor delivery of nanoparticles in mice using machine learning models

Nanoparticles (NPs) can be designed for targeted delivery in cancer nanomedicine, but the challenge is a low delivery efficiency (DE) to the tumor site. Understanding the impact of NPs' physicochemical properties on target tissue distribution and tumor DE can help improve the design of nanomedicines. Multiple machine learning and artificial intelligence models, including linear regression, support vector machine, random forest, gradient boosting, and deep neural networks (DNN), were trained and validated to predict tissue distribution and tumor delivery based on NPs' physicochemical properties and tumor therapeutic strategies with the dataset from Nano-Tumor Database. Compared to other machine learning models, the DNN model had superior predictions of DE to tumors and major tissues. The determination coefficients (R2) for the test datasets were 0.41, 0.42, 0.45, 0.79, 0.87, and 0.83 for DE in tumor, heart, liver, spleen, lung, and kidney, respectively. All the R2 and root mean squared error (RMSE) results of the test datasets were similar to the 5-fold cross validation results. Feature importance analysis showed that the core material of NPs played an important role in output predictions among all physicochemical properties. Furthermore, multiple NP formulations with greater DE to the tumor were determined by the DNN model. To facilitate model applications, the final model was converted to a web dashboard. This model could serve as a high-throughput pre-screening tool to support the design of new and efficient nanomedicines with greater tumor DE and serve as an alternative tool to reduce, refine, and partially replace animal experimentation in cancer nanomedicine research.

Glutathione-Scavenging Celastrol-Cu Nanoparticles Induce Self-Amplified Cuproptosis for Augmented Cancer Immunotherapy.

Cuproptosis is a novel copper-dependent programmed cell death. The efficacy of cuproptosis is highly dependent on intracellular copper accumulation and counteracted by a high level of glutathione (GSH) in tumor cells. Here, this work develops a self-amplified cuproptosis nanoparticles (Cel-Cu NP) using celastrol (Cel), a natural product isolated from medical plant. In Cel-Cu NP, Cel serves as a versatile copper ionophore, exhibiting an ideal coordination capacity toward copper ions without compromising the cuproptosis induction. Notably, Cel can simultaneously scavenge GSH content to amplify cuproptosis. Moreover, this self-amplified cuproptosis further activates immunogenic cell death (ICD) to elicit robust immune response. Combining with immune checkpoint blockade, Cel-Cu NP effectively eradicates metastatic tumors in a mouse lung metastasis model. This study provides an efficient nanomedicine by inducing self-amplified cuproptosis for robust immunotherapy.

Amorphous CaCO3-bioreactor for tumor microenvironment regulation to reinforce tumor chemoimmunotherapy

Developing efficient nanomedicines to modulate the immunosuppressive tumor microenvironment (TME) is a highly sought-after method for improving the adverse clinical outcomes of immunotherapy. In this study, we designed a novel tumor immune stimulatory nanomedicine to regulate the immunosuppressive TME in multiple directions. This nanomedicine is liposome-modified amorphous calcium carbonate (ACC) nanoparticles (referred to as CEL/ACC-LP NPs) loaded with chemotherapeutic medication celastrol (CEL). CEL/ACC-LP NPs explosively release calcium ions (Ca2+) and CEL in the tumor acidic microenvironment, and rapidly deplete H+ to alleviate the tumor acidic microenvironment, exhibiting intrinsic immune regulatory activity in synergistic tumor chemoimmunotherapy. CEL induces reactive oxygen species (ROS) to promote Ca2+ influx, exacerbating cellular Ca2+ overload. In addition, CEL/ACC-LP NPs can cause unique immunogenic cell death (ICD) effects. Therefore, the multi-directional regulation of tumor cells through simple nano preparation will offer a potent approach to improve the efficacy of chemoimmunotherapy.

Influence of albumin concentration on surface characteristics and cellular responses in the pre-incubation of multi-walled carbon nanotubes.

Reliable characterization of protein coronas (PCs) that form when nanomaterials are introduced into biological fluids is a critical step in the development of safe and efficient nanomedicine. We observed that bovine serum albumin (BSA)-coated multi-walled carbon nanotubes (MWCNTs) do not induce cytotoxicity, but have different cellular uptake rates depending on the BSA pretreatment concentration. To determine how these slight differences affect A549 cell responses and intracellular changes, we conducted spectroscopic (circular dichroism and Fourier-transform infrared) and spectrometric (nanoflow liquid chromatography-electrospray ionization-tandem mass spectrometry) analyses. The various characterization techniques conducted in this study reveal the following. (i) The composition ratio of PCs on MWCNTs differs depending on the BSA concentration. (ii) Analysis of the secondary structure of the proteins revealed that the α-helix structure increased with increasing BSA concentration. (iii) Proteomic analysis showed that different biological pathways were activated at levels higher and lower than 5 mg mL-1. Such combined spectroscopic and spectrometric approaches provide an integrated understanding of PC composition as well as how nano/bio-interface states are linked to cellular-level responses. Our results can support reliable and practical applications of nanomedicine development.

Rebamipide nanocrystal with improved physicomechanical properties and its assessment through bio-mimicking 3D intestinal permeability model.

This study investigated the formulation and characterization of rebamipide nanocrystals (REB-NCs) to enhance the solubility and permeability of rebamipide, an anti-ulcer medication known for its low aqueous solubility and permeability, classified as BCS class IV. Employing high-pressure homogenization and wet milling techniques, we successfully achieved nanonization of rebamipide, resulting in stable nanosuspensions that were subsequently freeze-dried to produce REB-NCs with an average particle size of 223 nm. Comprehensive characterization techniques, including Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) confirmed the crystalline nature of the nanocrystals and their compatibility with the selected excipients. The saturation solubility study revealed a remarkable three-fold enhancement in PBS pH 7.4 compared to rebamipide API, indicating the effectiveness of the nanocrystal formulation in improving drug solubility. Furthermore, 3D in-vitro permeability assessments conducted on Caco-2 cell monolayers demonstrated an noticeable increase in the permeability of REB-NCs relative to the pure active pharmaceutical ingredient (API), highlighting the promise of this formulation to enhance drug absorption. The dissolution profile of the nanocrystal tablets exhibited immediate release characteristics, significantly outperforming conventional formulations in terms of the dissolution rate. This research underscores the potential of nanomilling as a scalable, environment-friendly, and less toxic approach to significantly enhance the bioavailability of rebamipide. By addressing the challenges associated with the solubility and permeability of poorly water-soluble drugs, our outcome offers insightful information into developing efficient nanomedicine strategies for enhancing therapeutic outcomes.

Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles.

Most nanomedicines require efficient in vivo delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. We reviewed nanoparticle design and biological modulation strategies to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, we studied the preclinical literature from 2011-2021 and analyzed nanoparticle blood circulation and organ biodistribution data. Our findings revealed that nanoparticle surface chemistry affected the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improved the blood area under the curve by ~418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.

Cancer treatment therapies: traditional to modern approaches to combat cancers.

As far as health issues are concerned, cancer causes one out of every six deaths around the globe. As potent therapeutics are still awaited for the successful treatment of cancer, some unconventional treatments like radiotherapy, surgery, and chemotherapy and some advanced technologies like gene therapy, stem cell therapy, natural antioxidants, targeted therapy, photodynamic therapy, nanoparticles, and precision medicine are available to diagnose and treat cancer. In the present scenario, the prime focus is on developing efficient nanomedicines to treat cancer. Although stem cell therapy has the capability to target primary as well as metastatic cancer foci, it also has the ability to repair and regenerate injured tissues. However, nanoparticles are designed to have such novel therapeutic capabilities. Targeted therapy is also now available to arrest the growth and development of cancer cells without damaging healthy tissues. Another alternative approach in this direction is photodynamic therapy (PDT), which has more potential to treat cancer as it does minimal damage and does not limit other technologies, as in the case of chemotherapy and radiotherapy. The best possible way to treat cancer is by developing novel therapeutics through translational research. In the present scenario, an important event in modern oncology therapy is the shift from an organ-centric paradigm guiding therapy to complete molecular investigations. The lacunae in anticancer therapy may be addressed through the creation of contemporary and pertinent cancer therapeutic techniques. In the meantime, the growth of nanotechnology, material sciences, and biomedical sciences has revealed a wide range of contemporary therapies with intelligent features, adaptable functions, and modification potential. The development of numerous therapeutic techniques for the treatment of cancer is summarized in this article. Additionally, it can serve as a resource for oncology and immunology researchers.

Variations in metabolite profiles of serum coronas produced around PEGylated liposomal drugs by surface property.

Understanding biomolecular coronas that spontaneously occur around nanocarriers (NCs) in biological fluids is critical to nanomedicine as the coronas influence the behaviors of NCs in biological systems. In contrast to extensive investigations of protein coronas over the past decades, understanding of the coronas of biomolecules beyond proteins, e.g., metabolites, has been rather limited despite such biochemicals being ubiquitously involved in the coronas, which may influence the bio-nano interactions and thus exert certain biological impacts. In this study, serum biomolecular coronas, in particular the coronas of metabolites including lipids, around PEGylated doxorubicin-loaded liposomes with different surface property were investigated. The surface properties of liposomal drugs varied in terms of surface charge and PEGylation density by employing different ionic lipids such as DOTAP and DOPS and different concentrations of PEGylation lipids in liposome formulation. Using the liposomal drugs, the influence of the surface property on the serum metabolite profiles in the coronas was traced for target molecules of 220 lipids and 88 hydrophilic metabolites. From the results, it was found that metabolites rather than proteins mainly constitute the serum coronas on the liposomal drugs. Most of the serum metabolites were found to be retained in the coronas but with altered abundances. Depending on their class, lipids exhibited a different dependence on the surface property. However, overall, lipids appeared to favor corona formation on more negatively charged and PEGylated surfaces. Hydrophilic metabolites also exhibited a similar propensity for corona formation. This study on the surface dependence of metabolite corona formation provides a fundamental contribution toward attaining a comprehensive understanding of biomolecular coronas, which will be critical to the development of efficient nanomedicine.

Using surface plasmon resonance, capillary electrophoresis and diffusion-ordered NMR spectroscopy to study drug release kinetics

Nanomedicines, including polymer nanocarriers with controlled drug release, are considered next-generation therapeutics with advanced therapeutic properties and reduced side effects. To develop safe and efficient nanomedicines, it is crucial to precisely determine the drug release kinetics. Herein, we present application of analytical methods, i.e., surface plasmon resonance biosensor technology (SPR), capillary electrophoresis, and 1H diffusion-ordered nuclear magnetic resonance spectroscopy, which were innovatively applied for drug release determination. The methods were optimised to quantify the pH-triggered release of three structurally different drugs from a polymer carrier. The suitability of these methods for drug release characterisation was evaluated and compared using several parameters including applicability for diverse samples, the biological relevance of the experimental setup, method complexity, and the analysis outcome. The SPR method was the most universal method for the evaluation of diverse drug molecule release allowing continuous observation in the flow-through setting and requiring a small amount of sample.

An Extracellular Vesicle-Cloaked Multifaceted Biocatalyst for Ultrasound-Augmented Tendon Matrix Reconstruction and Immune Microenvironment Regulation.

The healing of tendon injury is often hindered by peritendinous adhesion and poor regeneration caused by the accumulation of reactive oxygen species (ROS), development of inflammatory responses, and the deposition of type-III collagen. Herein, an extracellular vesicles (EVs)-cloaked enzymatic nanohybrid (ENEV) was constructed to serve as a multifaceted biocatalyst for ultrasound (US)-augmented tendon matrix reconstruction and immune microenvironment regulation. The ENEV-based biocatalyst exhibits integrated merits for treating tendon injury, including the efficient catalase-mimetic scavenging of ROS in the injured tissue, sustainable release of Zn2+ ions, cellular uptake augmented by US, and immunoregulation induced by EVs. Our study suggests that ENEVs can promote tenocyte proliferation and type-I collagen synthesis at an early stage by protecting tenocytes from ROS attack. The ENEVs also prompted efficient immune regulation, as the polarization of macrophages (Mφ) was reversed from M1φ to M2φ. In a rat Achilles tendon defect model, the ENEVs combined with US treatment significantly promoted functional recovery and matrix reconstruction, restored tendon morphology, suppressed intratendinous scarring, and inhibited peritendinous adhesion. Overall, this study offers an efficient nanomedicine for US-augmented tendon regeneration with improved healing outcomes and provides an alternative strategy to design multifaceted artificial biocatalysts for synergetic tissue regenerative therapies.

Parkinson's Disease: Current Status, Diagnosis, and Treatment Using Nanomedicines

AbstractParkinson's disease (PD) is a chronic, and highly neurodegenerative disorder with complex pathological processes. The features for neuropathological identification of PD include α‐synuclein (α‐syn) protein aggregates, oxidative stress, metal ion dyshomeostasis, neurotransmitter deficiencies, and mitochondrial dysfunction. Currently, no definite treatment paradigm can completely cure PD patients, which is increasing globally over the past few decades. The existence of the blood‐brain barrier (BBB) restricts the conventional treatment processes and makes the therapeutic delivery to the brain a bit more challenging. Therefore, developing new useful medicines for improving brain distribution is vital to overcome BBB and helping the early diagnosis and treatment of PD. In this review, the current limitations of conventional drugs are highlighted and the development of new medicines to overcome such limitations is covered. This work will provide insight into the direction for designing novel efficient nanomedicines for the early diagnosis and treatment of PD.

Nanomaterial's interfacial stimulation of vascular endothelial cells and divergent guidances for nanomedicine treating vasculature-associated diseases

Blood vasculature plays an essential role in transporting nanomaterials in vivo. However, the interaction between vascular endothelial cells (VECs) and nanomaterials lacked deep understanding, impeding the development of safe and efficient nanomedicine. Here, we discover that VECs can be significantly stimulated by two-dimensional PEGylated lamellar materials (PLMs) without being internalized. Additional experiments and computational simulations suggest that the unique VEC stimulation can be ascribed to the interaction between the PLMs and the membrane lipids, which induces ion-transport-related conformational change of L-type calcium ion channel Cav1.3. Additionally, the in vivo studies demonstrate that PLMs-stimulated VECs have divergent impacts on two types of vasculature-associated diseases: exacerbating the development of atherosclerosis while magnifying the accumulation of nanomedicine within tumors. Thus, the current study not only advances our understanding of how specific proteins on VEC membranes could be stimulated by PLMs but also guides the rational use of promising PLMs in nanomedicine.

Cellular uptake and retention studies of silica nanoparticles utilizing senescent fibroblasts

Understanding the interplay between nanoparticles (NPs) and cells is essential to designing more efficient nanomedicines. Previous research has shown the role of the cell cycle having impact on the efficiency of cellular uptake and accumulation of NPs. However, there is a limited investigation into the biological fate of NPs in cells that are permanently withdrawn from the cell cycle. Here we utilize senescent WI-38 fibroblasts, which do not divide and provide a definitive model for tracking the biological fate of silica nanoparticles (SiNPs) independent of cell cycle. We use several methods to measure the cellular uptake kinetics and intracellular retention of SiNPs, including confocal laser scanning microscopy (CLSM), flow cytometry, and transmission electron microscopy (TEM). We demonstrate that SiNPs readily enter into senescent cells. Once internalized, SiNPs do not exit and accumulate in the cytoplasm for long term. Our study provides a basis for future development of NP-based tools that can detect and target senescent cells for therapy.

Remodeling the Tumor Microenvironment with Core-Shell Nanosensitizer Featuring Dual-Modal Imaging and Multimodal Therapy for Breast Cancer.

To improve the efficiency of radiation therapy (RT) for breast cancer, a designable multifunctional core-shell nanocomposite of FeP@Pt is constructed using Fe(III)-polydopamine (denoted as FeP) as the core and platinum particles (Pt) as the shell. The hybrid structure is further covered with hyaluronic acid (HA) to give the final nanoplatform of FeP@Pt@HA (denoted as FPH). FPH exhibits good biological stability, prolongs blood circulation time, and is simultaneously endowed with tumor-targeting ability. With CD44-mediated endocytosis of HA, FPH can be internalized by cancer cells and activated by the tumor microenvironment (TME). The redox reaction between Fe3+ in FPH and endogenous glutathione (GSH) or/and hydrogen peroxide (H2O2) initiates ferroptosis therapy by promoting GSH exhaustion and •OH generation. Moreover, FPH has excellent photothermal conversion efficiency and can absorb near-infrared laser energy to promote the above catalytic reaction as well as to achieve photothermal therapy (PTT). Ferroptosis therapy and PTT are further accompanied by the catalase activity of Pt nanoshells to accelerate O2 production and the high X-ray attenuation coefficient of Pt for enhanced radiotherapy (RT). Apart from the therapeutic modalities, FPH exhibits dual-modal contrast enhancement in infrared (IR) thermal imaging and computed tomography (CT) imaging, offering potential in imaging-guided cancer therapy. In this article, the nanoplatform can remodel the TME through the production of O2, GSH- and H2O2-depletion, coenhanced PTT, ferroptosis, and RT. This multimodal nanoplatform is anticipated to shed light on the design of TME-activatable materials to enhance the synergism of treatment results and enable the establishment of efficient nanomedicine.

Cationic phosphorus dendron nanomicelles deliver microRNA mimics and microRNA inhibitors for enhanced anti-inflammatory therapy of acute lung injury.

The development of efficient nanomedicines to repress the repolarization of M1 phenotype macrophages and therefore inhibit pro-inflammatory cytokine overexpression for anti-inflammatory therapy is still a challenging task. We report here an original gene delivery nanoplatform based on pyrrolidinium-modified amphiphilic generation 1 phosphorus dendron (C12G1) nanomicelles with a rigid phosphorous dendron structure. The nanomicelles display higher gene delivery efficiency than the counterpart materials of pyrrolidinium-modified G1 phosphorus dendrimers, and meanwhile exhibit excellent cytocompatibility. The C12G1 nanomicelles can be employed to co-deliver the miRNA-146a mimic (miR-146a mimic) and miRNA-429 inhibitor (miR-429i) to inhibit the Toll-like receptor-4 signaling pathway and p38 mitogen-activated protein kinase signaling pathway, respectively, thus causing repression of M1 phenotype alveolar macrophage polarization. The developed C12G1/miR-mixture polyplexes enable efficient therapy of lipopolysaccharide-activated alveolar macrophages in vitro and an acute lung injury mouse model in vivo. The generated cationic phosphorus dendron nanomicelles may hold promising potential for anti-inflammatory gene therapy of other inflammatory diseases.

Modulating Nanozyme-Based Nanomachines via Microenvironmental Feedback for Differential Photothermal Therapy of Orthotopic Gliomas.

Gliomas are common and refractory primary tumors closely associated with the fine structures of the brain. Photothermal therapy (PTT) has recently shown promise as an effective treatment for gliomas. However, nonspecific accumulation of photothermal agents may affect adjacent normal brain structures, and the inflammatory response induced during PTT may result in an increased risk of brain tumor recurrence or metastasis. Here, the design and fabrication of an intelligent nanomachine is reported based on Gd2 O3 @Ir/TMB-RVG29 (G@IT-R) hybrid nanomaterials. These nanomaterials enable tumor-specific PTT and eliminate inflammation to protect normal brain tissue. The mechanism involves the rabies virus glycopeptide-29 peptide (RVG29) passing through the blood-brain barrier (BBB) and targeting gliomas. In the tumor microenvironment, Ir nanozymes can act as logic control systems to trigger chromogenic reaction amplification of 3,3',5,5'-tetramethylbenzidine (TMB) for tumor-specific PTT, whereas in normal brain tissues, they scavenge reactive oxygen species (ROS) generated by poor therapy and function as protective agents. Autophagy inhibition of Gd2 O3 enables excellent photothermal therapeutic effects on orthotopic gliomas and protection against inflammation in normal cells. The results of this study may prove useful in developing highly efficient nanomedicines for glioma treatment.

Advancing intestinal organoid technology to decipher nano-intestine interactions and treat intestinal disease.

With research burgeoning in nanoscience and nanotechnology, there is an urgent need to develop new biological models that can simulate native structure, function, and genetic properties of tissues to evaluate the adverse or beneficial effects of nanomaterials on a host. Among the current biological models, three-dimensional (3D) organoids have developed as powerful tools in the study of nanomaterial-biology (nano-bio) interactions, since these models can overcome many of the limitations of cell and animal models. A deep understanding of organoid techniques will facilitate the development of more efficient nanomedicines and further the fields of tissue engineering and personalized medicine. Herein, we summarize the recent progress in intestinal organoids culture systems with a focus on our understanding of the nature and influencing factors of intestinal organoid growth. We also discuss biomimetic extracellular matrices (ECMs) coupled with nanotechnology. In particular, we analyze the application prospects for intestinal organoids in investigating nano-intestine interactions. By integrating nanotechnology and organoid technology, this recently developed model will fill the gaps left due to the deficiencies of traditional cell and animal models, thus accelerating both our understanding of intestine-related nanotoxicity and the development of nanomedicines.

A novel pH- and glutathione-responsive drug delivery system based on in situ growth of MOF199 on mesoporous organic silica nanoparticles targeting the hepatocellular carcinoma niche

BackgroundFor people with advanced hepatocellular carcinoma (HCC), systemic chemotherapy remains the only choice of palliative treatment. However, chemotherapy efficacy is not effective due to its short blood circulation times, nonspecific cell and tissue biodistribution, and rapid metabolism or excretion from the body. Therefore, a targeted nanomedicine delivery system is urgently needed.MethodsIn order to improve the treatment efficiency of HCC, based on in situ growth of a copper metal organic framework on mesoporous organic silica nanoparticles, dual pH- and glutathione (GSH)-responsive multifunctional nanocomposites were synthesized as nanocarriers for enhanced HCC therapy. In this research, cellular uptake studies were performed using CLSM and Bio-TEM observations. Flow cytometry, AO-EB fluorescent staining, EdU test and Western blot were utilized to explore the apoptosis and proliferation process. In vivo imaging was employed to research the distribution of the nanocomposites in HCC tumor-bearing nude mice and the xenograft model of HCC tumor-bearing nude mice was applied to investigate the anti-tumor effects of drug-loaded nanocomposites in vivo.ResultsThis newly constructed degradable nanocomposite DOX/SOR@SP94 and mPEG-anchored MONs@MOF199 (D/S@SPMM) has the benefits of controllable pore size, high encapsulation efficiency, and precise targeting. According to the results of in vivo imaging and anti-tumor studies, as well as pharmacokinetic research, D/S@SPMM possessed precise HCC tumor targeting and long-lasting accumulation properties at the tumor region. Compared with traditional chemotherapy and non-targeted drug delivery systems, anti-tumor efficiency was increased by approximately 10- and 5-fold, respectively. The nanocomposites exhibited excellent anti-tumor properties without inducing observable systemic toxicity, owing to efficient DOX and SOR loading and release as well as the HCC specific targeting peptide SP94.ConclusionsThe in vitro and in vivo anti-tumor results indicated that these nanocomposites could be an efficient nanomedicine for targeting HCC therapy.