Nanoparticle-mediated co-delivery systems have emerged as a pivotal area of research in biomedical sciences, offering innovative avenues for combination therapy. These systems are designed to simultaneously carry multiple therapeutic agents, effectively addressing challenges associated with traditional combination approaches, such as discrepancies in pharmacokinetics that result in uneven drug distribution. By leveraging precisely engineered nanoplatforms, researchers can achieve spatiotemporal control over the release of multiple drugs, thereby enhancing therapeutic efficacy while minimizing adverse effects. With continuous advancements in materials science and nanotechnology, the design of co-delivery systems has become increasingly sophisticated, equipping researchers with robust tools to tackle complex pathological conditions.
The fundamental principle of co-delivery lies in delivering multiple agents concurrently to achieve synergistic effects. In oncology, for example, the simultaneous administration of drugs with distinct mechanisms can target multiple pathways and molecular sites, amplifying the therapeutic outcome. Compared with monotherapy, combination strategies can more effectively address disease heterogeneity and complexity, offering significant potential to overcome multi-drug resistance.
Traditional combination therapy, however, faces major limitations due to the disparate pharmacokinetic profiles of individual drugs, which result in variable distribution, metabolism, and clearance rates. Maintaining an optimal drug ratio at the target site becomes challenging under such circumstances. Nanoparticle co-delivery systems circumvent this limitation by integrating multiple agents into a single nanocarrier, ensuring coordinated delivery to the same pathological cells at a predetermined ratio.
Nanoparticle platforms offer multiple advantages as carriers for combination therapy. They allow precise modulation of drug-loading ratios and enable encapsulated agents to overcome physiological and pathological barriers, achieving effective accumulation in target tissues or cells. Various nanocarriers, including liposomes, polymeric micelles, dendrimers, vesicles, and hydrogels, can improve the serum stability of loaded drugs, enhance biocompatibility, and prolong systemic circulation.
These nanocarriers can passively target pathological sites via the enhanced permeability and retention (EPR) effect and can be further engineered for active targeting through surface functionalization. One conceptual framework for anti-tumor nanoparticle delivery, the "five capabilities principle", articulates ideal features for nanocarriers: prolonged circulation (mobility), targeted accumulation (localization), deep tissue penetration (infiltration), efficient cellular internalization (uptake), and controlled drug release (release), which collectively define the optimal characteristics of nanoparticle-based systems.
Conventional multi-drug strategies face significant formulation and delivery limitations. Variations in the physicochemical properties of individual compounds often lead to inconsistent distribution profiles and uncontrolled release behaviors, making it challenging to sustain optimal component ratios within the intended delivery environment.
Moreover, the efficacy of combination therapies is closely dependent on the relative concentrations of the drugs involved. Specific ratios may produce synergistic effects, while deviations can lead to additive or even antagonistic interactions. Achieving such precision through conventional delivery methods is inherently difficult because each drug exhibits independent pharmacokinetic behavior.
Non-specific distribution of drugs in non-target tissues also increases the risk of dose-limiting toxicity, restricting the application of highly potent drug combinations. Nanoparticle co-delivery systems address these challenges by enabling targeted delivery, thereby enhancing therapeutic indices while reducing systemic toxicity.
Fig.1 Lung cancer co-delivery nanoparticle combinations overview1,2.
Conventional multi-drug strategies face inherent formulation and delivery challenges. Differences in physicochemical properties among agents often lead to inconsistent biodistribution and variable release behavior, making it difficult to maintain optimal ratios of multiple components within the intended target environment.
Moreover, the efficacy of combination therapies is closely dependent on the relative concentrations of the drugs involved. Specific ratios may produce synergistic effects, while deviations can lead to additive or even antagonistic interactions. Achieving such precision through conventional delivery methods is inherently difficult because each drug exhibits independent pharmacokinetic behavior.
Non-specific distribution of drugs in non-target tissues also increases the risk of dose-limiting toxicity, restricting the application of highly potent drug combinations. Nanoparticle co-delivery systems address these challenges by enabling targeted delivery, thereby enhancing therapeutic indices while reducing systemic toxicity.
Successful co-delivery requires tailored encapsulation strategies, designed based on the physicochemical characteristics of therapeutic agents (hydrophilicity, size, charge) and carrier properties. For hydrophobic and hydrophilic drug combinations, core-shell structures are frequently employed, allowing compartmentalization of drugs in distinct regions within the nanoparticle.
Advanced strategies include in situ confinement of metal nanoparticles within metal-organic frameworks (MOFs). For instance, stable Zr-MOF matrices can facilitate the reduction of metal ions (Au3+, Pd2+, Ag+) into nanoparticles under mild conditions without external reductants, creating multifunctional NP@MOF composites. This approach eliminates harsh synthesis conditions and opens avenues for constructing versatile co-delivery systems.
Applications extend beyond medicine. In agriculture, co-delivery systems have been developed to enhance plant protection by simultaneously delivering pathogen-targeting oligosaccharides and dsRNA constructs for gene silencing, improving efficacy while inducing systemic plant resistance.
Controlled release mechanisms are critical for ensuring that therapeutic agents are released at the appropriate time and location. These mechanisms often exploit environmental stimuli such as pH, enzymatic activity, redox potential, or temperature. Sequential release is particularly important in combination therapy, where the order of drug release may influence therapeutic outcomes, for example, releasing a sensitizing agent prior to a primary therapeutic agent.
External stimuli, such as ultrasound, can also guide targeted drug release. Innovations have demonstrated ultrasound-responsive nanoparticles capable of releasing drugs selectively at target sites, achieving optimal sensitivity and stability under physiological conditions.
Surface functionalization enhances nanoparticle targeting and biocompatibility. Ligand conjugation, including antibodies, peptides, or carbohydrates, can improve recognition and internalization by specific cell types. Both passive targeting (via size and surface properties) and active targeting (ligand-receptor interactions) are employed to maximize specificity.
Charge modulation is another effective strategy. In tumor microenvironments, negatively charged nanoparticle shells can expose positively charged cores under acidic conditions, promoting tissue penetration and cellular uptake. Such design leverages environmental characteristics for enhanced delivery efficiency.
As nanotechnology continues to advance, nanoparticle-mediated co-delivery systems hold significant promise across medicine and agriculture. By selecting appropriate materials, optimizing encapsulation strategies, implementing precise release control, and leveraging surface functionalization, researchers are creating intelligent, high-performance delivery systems that enhance combination therapy outcomes and pave the way for next-generation precision interventions.
BOC Sciences provides versatile nanoparticles with diverse compositions and functional modifications, customized solutions for your delivery needs.
Small molecule-small molecule co-delivery integrates two or more therapeutics with complementary mechanisms into a single nanoparticle platform to achieve synergistic pharmacological effects. In oncology research, for instance, the co-delivery of chemotherapeutic agents with immunomodulators enables simultaneous direct cytotoxic activity against tumor cells and activation of host immune responses.
Challenges such as the differential solubility of hydrophobic and hydrophilic drugs can be addressed through rational nanocarrier design. Lipid-polymer hybrid nanoparticles, for example, can encapsulate hydrophilic drugs within an aqueous core while loading hydrophobic drugs in the lipid shell, maintaining chemical stability and ensuring a controlled release ratio at the target site.
Table 1. Representative Small Molecule–Small Molecule Combinations.
| Combination Type | Representative Agents | Mechanism | Nanocarrier Form |
| Chemotherapy-Immunomodulator | Doxorubicin + Imiquimod | Cytotoxicity + Immune activation | Liposomal nanoparticles |
| Antioxidant-Chemotherapy | Paclitaxel + Quercetin | Apoptosis induction + oxidative stress protection | Polymeric micelles |
| Antibiotic Synergy | Vancomycin + Chloramphenicol | Cell wall inhibition + protein synthesis inhibition | Solid lipid nanoparticles |
Nanoparticle co-delivery can also combine traditional small molecules with biomacromolecules to achieve multi-tiered therapeutic interventions. Co-delivery of chemotherapeutic drugs with plasmid DNA, for example, allows concurrent cytotoxicity and gene modulation, enabling gene supplementation or correction while targeting diseased cells.
In drug–protein co-delivery, nanoparticles protect proteins such as enzymes or antibodies from degradation, prolong their half-life, and ensure synchronized delivery with small molecule drugs. Advanced strategies such as layer-by-layer self-assembly and multi-compartment nanocarriers have successfully addressed technical challenges associated with co-encapsulating therapeutics of differing physicochemical properties.
Co-encapsulation of siRNA with chemotherapeutics provides a synergistic approach combining gene silencing with chemical cytotoxicity. Delivery of siRNA targeting drug-resistance genes alongside chemotherapeutic agents can reverse cellular resistance mechanisms and substantially enhance drug efficacy.
Efficient co-encapsulation relies on carefully engineered carriers. Cationic liposomes or polymers can simultaneously accommodate negatively charged siRNA and hydrophobic chemotherapeutics, balancing loading efficiency while enabling sequential or synchronous release within the intracellular environment.
Table 2. Representative siRNA-Chemotherapy Co-Delivery Systems.
| Disease Model | siRNA Target | Chemotherapeutic | Synergistic Mechanism | Carrier Type |
| Breast Cancer | MDR1 gene | Paclitaxel | Inhibition of P-gp efflux pumps | Cationic liposome |
| Lung Cancer | Bcl-2 gene | Cisplatin | Promotion of apoptosis | Dendritic polymer |
| Liver Cancer | VEGF gene | Sorafenib | Anti-angiogenic effect | Polymeric nanoparticle |
Synergistic nanoformulations are designed to optimize functional complementarity and release kinetics of multiple components. For instance, co-delivery systems combining photothermal agents with chemotherapeutics can generate localized heat under near-infrared irradiation while triggering drug release, integrating physical and chemical modalities.
Advanced designs allow for sequential therapeutic cascades: a vascular-disrupting agent may be released first to enhance tumor permeability, followed by chemotherapeutics to penetrate deeper tissue layers. This temporal control markedly improves therapeutic efficiency.
Table 3. BOC Sciences Co-Delivery Nanoparticle Platforms.
| Nanoparticle Platform | Applicable Product Categories / Representative Combinations | Inquiry |
| Polymeric Nanoparticles | Small Molecule–Small Molecule (Paclitaxel + Quercetin); Drug–Gene Co-Delivery (Chemotherapeutic + Plasmid DNA); siRNA–Chemotherapy Co-Delivery (siRNA + Chemotherapeutic) | Inquiry |
| Lipid Nanoparticles | Small Molecule–Small Molecule (Vancomycin + Chloramphenicol); siRNA–Chemotherapy Co-Delivery (siRNA + Chemotherapeutic) | Inquiry |
| Liposomes | Small Molecule–Small Molecule (Doxorubicin + Imiquimod); Drug–Protein Co-Delivery (Chemotherapeutic + Antibody/Enzyme) | Inquiry |
| Polymeric Micelles | Small Molecule–Small Molecule (Paclitaxel + Quercetin) | Inquiry |
| Dendrimers | Drug–Gene Co-Delivery (Chemotherapeutic + Plasmid DNA); siRNA–Chemotherapy Co-Delivery (siRNA + Chemotherapeutic) | Inquiry |
| Hybrid Nanoparticles | Synergistic Nanoformulations (Photothermal agent + Chemotherapeutic) | Inquiry |
| Cationic Liposomes | siRNA–Chemotherapy Co-Delivery (siRNA + Chemotherapeutic) | Inquiry |
Nanoparticle-mediated combination therapy achieves synergy through multi-target modulation. Co-delivery systems can simultaneously influence multiple key nodes within disease networks, producing outcomes beyond the additive effect of single agents. In tumor models, drugs targeting both proliferative signaling and apoptosis resistance pathways can induce programmed cell death more effectively.
Multi-target intervention is crucial due to compensatory mechanisms and network redundancies. When one pathway is inhibited, cells may continue proliferating via alternative routes. Nanoparticle co-delivery ensures that multiple agents reach the same cell population simultaneously, preventing compensatory escape and achieving more complete pathological suppression.
Drug resistance is a major obstacle in effective therapy, and nanoparticle co-delivery offers strategies to address this challenge. Systems can simultaneously deliver therapeutic agents and resistance-modifying molecules, such as efflux pump inhibitors, restoring cellular sensitivity to drugs.
Alternatively, co-delivery of siRNA targeting resistance genes alongside conventional drugs enables dual-level intervention at both gene and protein levels, fundamentally blocking resistance mechanisms. Nanocarriers protect these sensitive biomolecules until they reach target cells, ensuring maximal functional impact.
Intracellular transport and release kinetics critically influence therapeutic outcomes. After endocytosis, nanoparticles traverse the endosome–lysosome pathway, where pH and enzymatic activity changes can trigger drug release.
Well-designed co-delivery systems exploit these microenvironmental cues for spatiotemporal control. For example, pH-sensitive carriers may release one drug in mildly acidic endosomes and a second drug in lysosomes, optimizing sequential action and enhancing synergy.
Nanoparticle co-delivery significantly improves bioavailability and pharmacokinetic profiles. Nanocarriers protect drugs from enzymatic degradation, oxidation, and immune recognition, extending circulation half-life. Surface functionalization with targeting ligands enhances accumulation at disease sites while minimizing distribution to healthy tissue.
Such pharmacokinetic optimization is particularly important for drugs with narrow therapeutic windows. By controlling release rates, nanoparticles maintain effective concentrations at target sites, avoiding fluctuations that could compromise efficacy or safety. This ability to sustain therapeutic levels is difficult to achieve with conventional delivery approaches.
Polymeric nanocarriers occupy a central role in co-delivery systems, with PLGA, PEG, and dendrimers being the most representative platforms. PLGA offers excellent biocompatibility and tunable degradation rates, featuring a hydrophobic core capable of efficiently encapsulating hydrophobic agents. Through molecular design, PLGA-based carriers can also accommodate hydrophilic drugs for simultaneous multi-agent delivery.
PEGylation remains a classical strategy for extending nanoparticle circulation time. PEG chains on the nanoparticle surface form a hydrated shell that minimizes protein adsorption and reduces immune recognition, thereby prolonging systemic persistence. Dendrimers, with their precisely branched architectures and abundant surface functional groups, provide an ideal platform for synchronized loading of multiple therapeutic agents.
Table 4. Comparative Features of Polymeric Nanocarriers.
| Material Type | Structural Features | Drug Loading Capacity | Degradation Profile | Suitable Agent Combinations |
| PLGA | Core–shell | High, ideal for hydrophobic drugs | Hydrolytic, tunable | Small molecule–small molecule |
| PEG | Linear or comb-shaped | Improved pharmacokinetics | Non-degradable or slow-degrading | Surface-modified carriers |
| Dendrimers | Highly branched | Multiple functional groups | Core-dependent | Drug–gene co-delivery |
Lipid-based nanoparticles are widely applied in co-delivery systems due to their biocompatibility and scalability. Liposomes, with their bilayer structure, can simultaneously encapsulate hydrophilic and hydrophobic drugs, and their phospholipid composition facilitates cellular uptake.
Solid lipid nanoparticles (SLNs), with a solid lipid core, offer enhanced physical stability and controlled-release characteristics. Modulating lipid composition and surface modifications allows precise regulation of drug release kinetics. Lipid-based carriers are particularly effective for co-encapsulation of nucleic acids and chemotherapeutic agents, as cationic lipids can condense nucleic acids into stable complexes.
Inorganic nanomaterials, such as mesoporous silica, gold nanoparticles, and magnetic iron oxides, provide unique physicochemical properties for co-delivery systems. Mesoporous silica, with its ordered pore structure and high surface area, enables high-capacity drug loading and surface functionalization for controlled release.
Hybrid nanomaterials combine organic and inorganic components to create multifunctional platforms. For example, a mesoporous silica core coated with a lipid layer retains the high loading capacity of inorganic materials while benefiting from the biocompatibility and functional versatility of lipids. Gold nanoparticles, leveraging surface plasmon resonance, can integrate photothermal effects with controlled drug release for synergistic applications.
Encapsulation efficiency is a critical metric for evaluating co-delivery systems, reflecting the carrier's capacity to load therapeutic agents. High-performance liquid chromatography (HPLC) is widely used to separate free drugs from nanoparticle-bound drugs and calculate encapsulation rates. Stability assessments include physical, chemical, and storage stability evaluations.
Dynamic light scattering (DLS) monitors nanoparticle size and distribution changes, while ζ-potential measurements indicate surface charge characteristics. Variations in these parameters during storage can signal aggregation or drug leakage risks. Accelerated stability testing under elevated temperature or mechanical stress predicts real-world shelf life.
In vitro co-release studies simulate the release behavior of multiple agents under physiological conditions. Common techniques include dialysis bags and Franz diffusion cells, with periodic sampling to quantify each agent in the release medium. This approach provides insight into drug release kinetics and temporal coordination between co-delivered agents.
To better mimic in vivo conditions, researchers employ release media with variable pH or enzyme content, enabling the assessment of environment-responsive nanoparticle release behavior. These studies provide essential data for predicting in vivo performance.
Table 5. BOC Sciences Co-Delivery Nanoparticle Characterization Service Portfolio.
| Service Area | Analytical Method | Measurable Parameters | Key Features / Benefits | Inquiry |
| Encapsulation Efficiency Analysis | HPLC / UV-Vis | Drug loading, encapsulation rate | Highly accurate quantitative measurement, sensitive detection for precise formulation evaluation | Inquiry |
| Particle Size & Distribution Characterization | Dynamic Light Scattering (DLS) | Average particle size, polydispersity index (PDI) | Rapid, non-destructive analysis for quality control and formulation optimization | Inquiry |
| In Vitro Drug Release Profiling | Dialysis Sampling / Release Assays | Release curves, release rates of multiple agents | Mimics physiological conditions, enables kinetic profiling of co-delivery systems | Inquiry |
| Synergy Evaluation of Multi-Agent Formulations | Combination Index (CI) Analysis | CI values, degree of synergistic effect | Quantitative assessment of combinatorial performance, guides optimal drug ratio selection | Inquiry |
Imaging and tracking techniques provide direct evidence of nanoparticle biodistribution and intracellular fate. Fluorescent labeling is commonly employed, allowing simultaneous visualization of multiple agents via distinct fluorescent tags.
Advanced imaging technologies, such as live-cell confocal microscopy, super-resolution microscopy, and in vivo imaging systems, enable tracking from individual cell to whole-animal scales. Radiolabeling provides quantitative distribution data and is particularly useful for preclinical pharmacokinetic studies.
Quantitative assessment of synergy is crucial for optimizing drug ratios in co-delivery systems. The combination index (CI) method is widely used, with CI < 1 indicating synergy, CI=1 indicating additive effects, and CI>1 indicating antagonism. Systematic screening of CI values across various drug ratios identifies optimal synergistic combinations.
Other methods, such as isobologram analysis and response surface modeling, integrate dose–effect relationships and drug interactions, providing a comprehensive evaluation of synergy and guiding formulation optimization for co-delivery nanoparticles.
Nanoparticle-mediated co-delivery systems offer a precise and controllable strategy for combination therapy by integrating multiple therapeutic agents within a single platform. Through rational selection of carrier materials, optimized encapsulation, controlled or sequential release, and surface functionalization, these systems enhance drug accumulation, improve pharmacokinetics, and enable multi-target modulation. Such approaches increase therapeutic efficacy while minimizing off-target effects, expanding opportunities for addressing complex disease mechanisms.
BOC Sciences leverages extensive expertise in nanoparticle co-delivery, providing end-to-end solutions from material design and nanocarrier fabrication to multi-agent encapsulation, release control, and quantitative evaluation of synergistic effects. Our portfolio spans polymeric, lipid-based, and hybrid nanoplatforms, offering customizable products and analytical services to support efficient, precise, and high-performance co-delivery strategies for research and industrial applications.
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