With the rapid advancement of nanotechnology, lipid nanoparticles (LNPs) have emerged as highly promising carriers in anticancer drug delivery systems. Owing to their distinctive physicochemical properties and favorable biocompatibility, LNPs can effectively address key limitations of conventional chemotherapeutic agents, including poor solubility, low bioavailability, and nonspecific toxicity. To understand the value of lipid nanoparticles in cancer-focused delivery strategies, it is essential to first examine their structural composition and the fundamental biological characteristics of cancer as a target.
Lipid nanoparticles are lipid-based delivery systems with particle sizes typically ranging from 10 to 200 nm. Unlike traditional liposomes, modern LNPs generally possess more complex internal architectures. Rather than simple bilayer vesicles, they often form dense core structures stabilized through electrostatic and hydrophobic interactions. Lipid nanoparticles are typically composed of ionizable lipids, helper lipids, cholesterol, and PEGylated lipids, each serving a distinct yet complementary function.
Ionizable lipids enable efficient cargo encapsulation and pH-responsive charge conversion, supporting intracellular release. Helper lipids stabilize the nanoparticle structure and maintain ordered lipid organization, while cholesterol enhances membrane fluidity and overall stability. PEGylated lipids form a protective surface layer that reduces aggregation, minimizes nonspecific interactions, and extends circulation persistence, collectively enabling robust and efficient delivery performance.
A defining advantage of LNPs is their strong encapsulation and protective capability. They can efficiently load hydrophobic small-molecule compounds or negatively charged nucleic acids (such as mRNA and siRNA), shielding them from enzymatic degradation. In addition, LNP components are typically biodegradable and biocompatible, with metabolic byproducts exhibiting minimal systemic burden.
Cancer is characterized by uncontrolled cell growth and division, primarily driven by genetic alterations that disrupt normal signaling pathways. From a delivery perspective, cancerous tissues exhibit a distinct tumor microenvironment (Tumor Microenvironment, TME) that differentiates them from healthy tissues. The TME is commonly associated with abnormal vasculature, insufficient lymphatic drainage, dense extracellular matrix, and mildly acidic conditions. While these features hinder the penetration of conventional therapeutics, they also create opportunities for nanoparticle-based targeting strategies.
Based on histological origin, cancer can be broadly classified into several categories, each displaying different nanoparticle uptake characteristics:
Carcinomas: Originating from epithelial tissues, such as lung and breast cancers, these are the most extensively studied targets for LNP-based delivery.
Sarcomas: Derived from mesenchymal tissues, including bone and muscle, these tumors often possess dense stromal structures that demand enhanced penetration capabilities.
Leukemia and lymphoma: Arising from the hematopoietic or lymphatic systems, these liquid tumors place greater emphasis on nanoparticle stability in circulation and selective recognition of suspended cells.
The ability of LNPs to selectively act on cancer cells relies on carefully engineered targeting and delivery mechanisms. This process encompasses circulation, tumor recognition, cellular attachment, membrane translocation, and intracellular release.
LNP-mediated tumor targeting generally involves two complementary strategies: passive targeting and active targeting.
Passive Targeting and the EPR Effect: Passive targeting leverages the unique anatomical and physiological characteristics of solid tumors. Rapid and disorganized angiogenesis results in leaky vasculature with enlarged endothelial gaps, typically ranging from 100 to 800 nm, combined with poor lymphatic drainage. This phenomenon, known as the enhanced permeability and retention (EPR) effect, enables appropriately sized LNPs to extravasate into tumor tissue and accumulate locally with limited clearance.
Active Targeting and Ligand Modification: To further enhance specificity, LNP surfaces can be functionalized with targeting ligands that selectively bind to receptors overexpressed on cancer cell membranes. Common active targeting approaches include:
Antibodies and antibody fragments: Leveraging high-affinity antigen–antibody interactions, such as antibodies targeting HER2 receptors in breast cancer.
Peptides and proteins: For example, transferrin receptors are frequently upregulated on cancer cells, and transferrin-modified LNPs can enhance cellular uptake.
Small-molecule ligands: Folic acid is a widely used ligand due to the elevated folate demand of rapidly proliferating cancer cells, enabling receptor-mediated internalization.
Once bound to the cell surface, LNPs are primarily internalized via receptor-mediated endocytosis, forming intracellular vesicles known as endosomes.
Fig.1 Diagram of passive and active targeting of lipid nanoparticles (BOC Sciences Original).
The interaction between LNPs and cancer cell membranes is a critical physicochemical step in effective delivery. Beyond receptor–ligand binding, this interaction is influenced by electrostatic forces and lipid exchange. Cell membranes generally carry a net negative charge due to glycocalyx components and phospholipid head groups. Early designs favored permanently cationic lipids to promote nonspecific electrostatic attraction; however, such systems often exhibited aggregation and undesired interactions during circulation. Modern LNPs address this challenge through ionizable lipids:
Circulation phase: At physiological pH (~7.4), LNPs remain near-neutral, reducing nonspecific membrane interactions.
Microenvironmental exposure: Upon reaching the mildly acidic tumor microenvironment or entering acidic endosomes, ionizable lipids become protonated, shifting the surface charge to positive.
Membrane fusion and disruption: Positively charged lipids interact strongly with negatively charged endosomal membranes, destabilizing their structure. This interaction promotes lipid fusion or the formation of non-bilayer phases, compromising membrane integrity and facilitating cargo release.
Accumulation near tumor vasculature alone is insufficient; effective delivery requires deep penetration into tumor cores. Several factors govern LNP penetration and efficiency.
Impact of Particle Size: Particle size is a key determinant of penetration depth. Smaller nanoparticles (below 50 nm) exhibit enhanced diffusion within dense tumor matrices and can reach hypoxic regions distant from blood vessels, but may be cleared rapidly by renal filtration. Larger particles (above 150 nm) are more prone to uptake by the reticuloendothelial system and face diffusion limitations. As a result, size optimization represents a balance between circulation persistence and tissue penetration.
Surface Property Modulation: Surface charge and hydrophilicity directly influence penetration behavior. PEGylation extends circulation time but can create the so-called "PEG dilemma," where dense PEG layers hinder cellular uptake and endosomal escape. To overcome this limitation, cleavable PEG-lipids are often employed. These designs allow PEG detachment in response to local acidic conditions or enzymatic activity, exposing functional structures that enhance membrane interaction and internalization.
The ultimate purpose of LNPs as delivery platforms is to enable efficient drug loading and controlled release.
Drug Loading Strategies: The structural versatility of LNPs allows simultaneous loading of compounds with different properties.
Hydrophobic drugs: Compounds such as paclitaxel or doxorubicin can be incorporated into the hydrophobic lipid core or embedded within lipid layers.
Hydrophilic drugs and nucleic acids: Negatively charged macromolecules, including RNA and DNA, are complexed with positively charged ionizable lipids under controlled pH conditions to form dense cores, which are subsequently encapsulated by lipid shells. This approach often achieves encapsulation efficiencies exceeding 90%.
Drug Release Mechanisms: An ideal LNP system remains stable during circulation and releases its payload only after cellular uptake. Key release mechanisms include:
pH-responsive release: Following endocytosis, the endosomal pH decreases to approximately 5.0–6.0. Protonation of ionizable lipids triggers structural transitions and disassembly, enabling rapid payload release and facilitating endosomal escape.
Enzyme-triggered release: Specific intracellular enzymes can cleave designed chemical bonds within LNP structures, initiating drug release.
Glutathione (GSH)-responsive release: Intracellular glutathione concentrations are significantly higher than extracellular levels. Incorporating disulfide bonds into LNP structures allows reductive cleavage in the cytosol, leading to nanoparticle disassembly and drug liberation.
BOC Sciences offers advanced lipid nanoparticle platforms with tunable compositions and surface functionalization to support targeted delivery research.
Contemporary research efforts are primarily dedicated to addressing the limitations of first-generation LNP systems, including insufficient targeting capability, low endosomal escape efficiency, and limited circulation stability. As a result, the field has moved toward increasingly diversified and fine-tuned design strategies.
Table 1. Comparative evolution of major research themes in lipid nanoparticles for cancer applications.
| Research dimension | Traditional focus | Current and emerging frontiers |
| Lipid material design | Synthesis of cationic lipids with emphasis on charge–charge interactions | Development of novel ionizable lipids emphasizing biodegradability, low immunogenicity, and optimized pKa values to maximize endosomal escape |
| Targeting strategies | Reliance on the EPR effect (passive targeting) and simple folate or transferrin modification | Dual-targeting or stimulus-responsive approaches (enzyme-, pH-, or light-responsive), using peptides, aptamers, or antibody fragments to achieve subcellular localization |
| Cargo types | Primarily small-molecule chemotherapeutics (e.g., doxorubicin, paclitaxel) | Shift toward macromolecular cargos (mRNA, siRNA, nucleic acid complexes) and co-delivery systems (small molecules plus nucleic acids, or immune modulators plus antigens) |
| Structural regulation | Simple lipid bilayer vesicles | Complex core–shell architectures or solid lipid nanoparticles (SLNs), with internal assembly precisely controlled via microfluidic technologies |
The maturation of LNP technology has significantly expanded therapeutic strategies, moving beyond direct cytotoxic mechanisms toward modulation of underlying biological processes.
mRNA-based cancer vaccine delivery platforms: LNPs are used to encapsulate mRNA encoding tumor-specific neoantigens. After uptake by antigen-presenting cells (APCs), such as dendritic cells, the mRNA is translated in the cytoplasm, and the resulting antigens are displayed on the cell surface. This process initiates a robust, antigen-specific T-cell response, guiding the immune system to recognize and eliminate cancer cells throughout the body.
Delivery of nucleic acid–based gene regulation tools: Direct modulation of oncogenic or tumor-suppressive genes represents a promising strategy for cancer intervention. LNPs have been developed to encapsulate nucleic acid–based gene regulation tools, such as mRNA, siRNA, or other synthetic ribonucleoprotein complexes. Rationally designed LNPs can protect these labile components and deliver them to the nucleus or cytoplasm, enabling targeted suppression, correction, or activation of specific genes implicated in tumor growth and survival.
Immune remodeling of the tumor microenvironment (TME): Beyond directly targeting cancer cells, LNPs are increasingly applied to deliver cytokines (e.g., IL-12) or immune checkpoint modulators (such as anti-PD-1/PD-L1 antibodies or their encoding nucleic acids) to tumor sites. This approach aims to convert immunosuppressive "cold" tumors into immunologically active "hot" tumors, thereby enhancing endogenous anti-tumor responses.
Recent studies have revealed new mechanisms for controlling the in vivo behavior of LNPs, particularly in the area of organ-specific targeting.
Selective Organ Targeting (SORT) technology: By introducing a fifth auxiliary component, referred to as a SORT molecule, into a standard four-component LNP formulation, researchers can precisely modulate biodistribution profiles. For example, incorporating lipids with specific charge properties enables preferential accumulation in organs such as the lung, spleen, or liver without relying on antibody ligands. This discovery provides a new physicochemical strategy for targeted delivery to organs associated with diseases such as lung or liver cancer.
In situ generation of CAR-T cells: Conventional CAR-T approaches require ex vivo modification of T cells, a process that is costly and operationally complex. Recent work demonstrates that T-cell-targeted LNPs, functionalized with CD3 or CD5 antibodies and loaded with mRNA encoding chimeric antigen receptors (CARs), can be administered directly. These LNPs selectively recognize circulating T cells and reprogram them in vivo, enabling localized generation of CAR-T cells and substantially simplifying the overall workflow.
The development of high-performance, tumor-targeted LNPs is a multidisciplinary systems process spanning chemical synthesis, formulation engineering, and biological validation. Key technical service modules required throughout research and development are outlined below.
This stage forms the foundation of LNP construction, with the primary objective of producing particles with uniform physicochemical properties through precise process control.
High-throughput lipid screening and formulation design: Design of Experiment (DoE) methodologies are applied to systematically optimize the molar ratios of ionizable lipids, helper lipids, cholesterol, and PEG-lipids. Critical parameters include the nitrogen-to-phosphorus (N/P) ratio, defined as the proportion of ionizable amines in lipids to phosphate groups in nucleic acids, which directly affects encapsulation efficiency and cytotoxicity.
Microfluidic mixing technologies: Microfluidics has become the mainstream approach for producing high-quality LNPs. By precisely controlling the mixing dynamics and flow conditions of the aqueous phase (containing cargo) and the organic phase (containing lipids) within micron-scale channels, rapid self-assembly of lipid components is induced. This method yields nanoparticles with narrow size distributions (PDI < 0.2), high batch-to-batch consistency, and excellent encapsulation efficiency.
To impart specific targeting capabilities, LNP surfaces require precise and controllable modification.
Post-insertion techniques: This mild functionalization strategy involves first preparing pre-formed LNPs, followed by co-incubation with ligand-conjugated lipids (e.g., DSPE-PEG-Ligand micelles). Under appropriate conditions, functional lipids spontaneously insert into the outer lipid layer, minimizing ligand degradation that may occur under harsh synthesis conditions.
Click chemistry and covalent conjugation: For applications requiring high stability, covalent coupling can be achieved via reactive groups on PEG termini (e.g., maleimide, NHS ester, or azide) and corresponding ligands such as antibodies or peptides. Click chemistry is particularly advantageous due to its rapid kinetics, high yield, and minimal by-products, enabling site-specific modification of complex ligands.
Table 2. Lipid Nanoparticle Technical Service Portfolio.
| Service | Description | Price |
| LNP Formulation | Systematic optimization of ionizable lipids, helper lipids, cholesterol, and PEG-lipid ratios using Design of Experiments (DoE) approaches, with precise control of the N/P ratio. | Inquiry |
| LNP Manufacturing Service | Production of self-assembled LNPs using microfluidic mixing technology, ensuring high batch-to-batch consistency and narrow particle size distribution (PDI < 0.2). | Inquiry |
| LNP Surface Functionalization Service | Precise modification with antibodies, peptides, or small-molecule ligands via post-insertion or covalent conjugation strategies. | Inquiry |
| LNP Characterization Service | Comprehensive analysis of particle size, PDI, zeta potential, and morphology to verify formulation stability and structural consistency. | Inquiry |
| Encapsulation Efficiency Analysis | Quantitative evaluation of nucleic acid and small-molecule payloads using RiboGreen assays or HPLC methods. | Inquiry |
| LNP Cellular Uptake and Endosomal Escape Analysis | Quantitative assessment of endocytosis efficiency and intracellular localization using flow cytometry and confocal microscopy. | Inquiry |
| Tumor Microenvironment–Adapted LNP Development Service | Customized LNP design tailored to acidic conditions, dense extracellular matrices, or immunosuppressive tumor microenvironments (TME). | Inquiry |
Following fabrication, LNPs must undergo multidimensional physicochemical characterization to confirm alignment with design specifications.
Table 3. Key physicochemical parameters and analytical techniques for lipid nanoparticles.
| Parameter | Scientific significance | Common analytical methods |
| Particle size and PDI | Influences biodistribution; PDI reflects particle uniformity | Dynamic light scattering (DLS) |
| Zeta potential (surface charge) | Affects colloidal stability, circulation time, and cellular interaction | Electrophoretic light scattering (ELS) |
| Morphology | Confirms solid, vesicular, or multilamellar structures | Cryogenic transmission electron microscopy (Cryo-TEM) |
| Encapsulation efficiency (EE%) | Indicates cargo utilization and formulation quality | RiboGreen assay (nucleic acids) / HPLC (small molecules) |
| Ligand density | Determines binding affinity and targeting performance | Fluorescence spectroscopy / Surface plasmon resonance (SPR) |
Before advancing to higher-level development stages, rigorous laboratory-based validation is required.
Release kinetics studies: Drug release profiles are evaluated under simulated physiological conditions (pH 7.4) and acidic environments (pH 5.0–6.0) using dialysis or centrifugal ultrafiltration methods. Key considerations include stability at neutral pH and responsive release under acidic conditions.
Cell-level biological performance assessment:
Cellular uptake studies: Flow cytometry or confocal microscopy is used to track the internalization efficiency and intracellular localization of fluorescently labeled LNPs, including assessment of endosomal escape.
Cytotoxicity and gene modulation efficiency: MTT or CCK-8 assays are applied to quantify effects on cancer cell viability (IC50 values). For nucleic acid cargos, qPCR or Western blot analysis is used to evaluate target gene expression or knockdown efficiency.
Lipid nanoparticles have emerged as versatile delivery platforms across diverse cancer types. Researchers design tailored delivery strategies based on the specific pathophysiological characteristics of each tumor.
Breast cancer is one of the most mature areas of LNP research, particularly for subtypes exhibiting multidrug resistance (MDR) or high receptor expression.
Overcoming multidrug resistance: A major cause of chemotherapy failure in MDR breast cancer is the overexpression of efflux pumps, such as P-glycoprotein (P-gp), which actively expel drugs from tumor cells. LNPs enter cells primarily via endocytosis, bypassing passive diffusion and avoiding direct interaction with membrane-bound efflux pumps. This mechanism significantly increases intracellular drug concentrations.
HER2 receptor targeting: For HER2-positive breast cancer, LNPs surface-modified with anti-HER2 antibody fragments (e.g., trastuzumab fragments) provide active targeting. This approach enhances tumor cell recognition and promotes rapid drug internalization through receptor-mediated endocytosis.
Co-delivery strategies: Breast cancer research frequently employs co-delivery, where a single LNP carries both a chemotherapeutic (e.g., doxorubicin) and a nucleic acid therapeutic (e.g., siRNA targeting anti-apoptotic genes). This "gene-chemotherapy combination" synergistically enhances tumor cell killing.
Lung cancer, particularly non-small cell lung cancer (NSCLC), faces challenges including systemic toxicity and difficulty reaching deep pulmonary tumors. LNP advances focus on inhalation-based delivery systems.
Inhalation and mucus penetration: Unlike intravenous drugs, inhalable LNPs directly target the lungs. Surface modifications, such as high-density PEG or mucus-inert polymers, help nanoparticles penetrate thick airway mucus and evade mucociliary clearance.
Precise intervention for gene mutations: For common lung cancer mutations (e.g., EGFR or KRAS), LNPs deliver nucleic acid therapeutics such as siRNA or mRNA. By suppressing oncogenic gene expression, these LNPs can inhibit tumor proliferation at the source, offering new avenues for patients unable to tolerate intensive chemotherapy.
Table 4. LNP Products for Targeted Cancer Delivery.
| Product | Description | Price |
| Ionizable LNP | Constructed with ionizable lipids that remain near-neutral under physiological conditions and undergo charge conversion in acidic endosomal environments, enabling high encapsulation efficiency and efficient endosomal escape; suitable for mRNA, siRNA, and other nucleic acid delivery applications. | Inquiry |
| PEGylated LNP | Incorporates PEGylated lipids on the particle surface to reduce nonspecific protein adsorption, prolong systemic circulation time, and enhance tumor accumulation, supporting EPR effect–driven passive targeting strategies. | Inquiry |
| Cleavable PEG-LNP | Utilizes cleavable PEG-lipids that detach under tumor microenvironment or endosomal conditions, balancing long circulation persistence with enhanced cellular uptake efficiency. | Inquiry |
| Folate-LNP | Surface-modified with folate ligands to enable folate receptor–mediated endocytosis, achieving active targeting of highly proliferative tumor cells. | Inquiry |
| pH-sensitive LNP | Designed with acid-sensitive lipids or architectures that undergo structural transitions in acidic tumor microenvironments or endosomes, enabling intelligent and triggered payload release. | Inquiry |
| Co-delivery LNP | A single LNP platform capable of simultaneously delivering chemotherapeutic small molecules and nucleic acid therapeutics, enabling synergistic gene regulation and chemotherapy effects. | Inquiry |
| Inhalable LNP | An LNP system optimized for pulmonary delivery with mucus-penetrating properties, suitable for lung cancer–related nucleic acid or drug delivery. | Inquiry |
| Intraperitoneal LNP | Designed for intraperitoneal administration, offering enhanced local retention and suitability for ovarian cancer peritoneal metastasis models. | Inquiry |
| Stroma-penetrating LNP | Engineered with small particle size or matrix-modulating designs to improve tissue penetration in dense tumor stroma, such as that found in pancreatic cancer. | Inquiry |
Gastrointestinal cancers, including gastric and colorectal cancers, often feature complex tumor microenvironments with acidic pH and dense extracellular matrices.
pH-responsive intelligent release: LNPs can be designed to respond to the mildly acidic tumor environment (pH < 6.8). Stable in circulation (pH 7.4), these nanoparticles undergo conformational changes upon entering acidic intracellular compartments, triggering rapid drug release. This strategy reduces off-target toxicity in normal intestinal tissues.
Matrix-penetrating capability: GI tumors often exhibit dense stroma. Research focuses on small-sized LNPs (<50 nm) or those modified with collagenase to degrade extracellular matrices, enhancing deep tissue penetration.
Ovarian cancer frequently spreads within the peritoneal cavity and exhibits resistance to platinum-based drugs in advanced stages. LNP applications target local delivery and gene-sensitization.
Intraperitoneal delivery: Direct injection of LNPs into the peritoneal cavity increases local drug concentration while minimizing systemic exposure. The retention properties of LNPs allow prolonged action on micro-metastases throughout the cavity.
Reversing drug resistance: LNPs carrying nucleic acids targeting resistance genes (e.g., MDR1 or DNA repair genes) can re-sensitize previously resistant ovarian cancer cells, improving the efficacy of subsequent chemotherapy.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely dense desmoplastic stroma, creating a significant barrier to therapy.
Overcoming stromal barriers: LNPs co-delivering stromal-degrading agents (e.g., hyaluronidase) and chemotherapeutics create channels in the tumor matrix, facilitating drug penetration.
Targeting KRAS mutations: Over 90% of PDAC patients carry KRAS mutations, which are traditionally "undruggable". LNPs encapsulating nucleic acids targeting mutant KRAS mRNA offer a promising approach to suppress tumor growth.
Table 5. Key LNP Strategies Across Cancer Types.
| Cancer Type | Main Pathological Challenge | LNP Strategy | Typical Cargo |
| Breast cancer | MDR, HER2 overexpression | Active targeting, efflux bypass | Chemotherapy + anti-apoptotic siRNA |
| Lung cancer | Deep tumor location, mucus barrier | Inhalation delivery, mucus-penetrating modification | Nucleic acids targeting EGFR/KRAS |
| Colorectal cancer | Acidic microenvironment, off-target toxicity | pH-sensitive design, colon targeting | Chemotherapy + immune modulators |
| Ovarian cancer | Peritoneal metastasis, platinum resistance | Intraperitoneal injection, long retention | Platinum drugs + resistance-reversing siRNA |
| Pancreatic cancer | Dense stromal barrier | Stromal depletion, KRAS gene silencing | Hyaluronidase + gemcitabine/siRNA |
LNPs are increasingly preferred due to their combination of targeting precision, drug protection, and safety.
Reducing systemic toxicity: Encapsulation in LNPs alters drug biodistribution, concentrating agents in tumors and minimizing exposure to healthy organs.
Cellular and subcellular targeting: Surface ligands allow recognition of specific cancer cells and precise intracellular delivery, e.g., to mitochondria or the nucleus, maximizing efficacy per dose.
Solubility enhancement: Hydrophobic anticancer compounds are stably incorporated into the lipid core, improving systemic delivery.
Protection of nucleic acids: LNPs shield mRNA or siRNA from enzymatic degradation and facilitate endosomal escape, preserving biological activity.
Natural and metabolizable components: LNPs are composed of phospholipids and cholesterol, which are endogenous or naturally metabolized, avoiding long-term accumulation.
Low immunogenicity: PEG-modified LNPs evade immune recognition, minimizing complement activation and macrophage uptake, prolonging circulation and reducing infusion-related reactions.
