Lipid-polymer hybrid nanoparticles: a cutting-edge frontier in breast cancer treatment strategies

ABSTRACT

Breast cancer remains one of the most prevalent and deadly cancers worldwide, affecting women. This review explores the potential of lipid-polymer hybrid nanoparticles (LPHNPs) as a next-generation drug delivery system for breast cancer therapy. The review categorizes LPHNPs and discusses their unique structure, preparation methods, and applications in cancer therapy. It delves into the various methods of preparing for LPHNPs. Furthermore, it examines the application of LPHNPs in treating various cancers, focusing on breast cancer, where they have shown promise in delivering single drugs, drug combinations, and nucleic acids like siRNA and miRNA. The ability of LPHNPs to overcome drug resistance and enhance therapeutic efficacy is emphasized, along with their potential for personalized medicine. The literature search was performed using PubMed, Scopus, and Web of Science databases to identify relevant studies published from 2009 to 2025. The review summarizes recent patents related to breast cancer treatment, showcasing advancements in drug delivery systems and therapeutic approaches. The conclusion underscores the transformative potential of LPHNPs in revolutionizing breast cancer treatment, provided that challenges in formulation, scalability, and long-term safety are addressed. Continued research and collaboration between researchers, clinicians, and regulatory bodies are essential to realize the benefits of LPHNPs in personalized cancer therapy.

1. Introduction

Breast cancer is among the utmost common cancers globally. In 2022, roughly 2.3 million women globally were diagnosed with breast cancer, consequential in 670,000 fatalities [1], predominantly women, though it can also affect men. The condition arises when these cells multiply uncontrollably, forming a tumor that can usually be identified through imaging or physical exams. Advances in early detection and treatment have greatly enhanced survival rates, underscoring the importance of awareness and knowledge about breast cancer for effective prevention and management [2].

Triple-Negative Breast Cancer (TNBC) is a highly aggressive subtype that lacks estrogen receptors, progesterone receptors, and HER2 protein, making treatment more difficult. HER2-positive breast Cancer is defined by the overexpression of the HER2 protein, which accelerates cancer cell growth and spreads rapidly, though it can be treated with targeted therapies. Inflammatory Breast Cancer (IBC) is a rare and aggressive type that leads to redness, swelling, and warmth in the breast due to obstructed lymph vessels. Paget’s Disease of the Breast, another uncommon form, involves the nipple and areola skin and is frequently linked to DCIS or invasive cancer [3].

The stages of breast cancer are classified based on the tumor’s size, whether it has spread to lymph nodes, and if it has metastasized to distant organs depicted in Figure 1. Stage 0 describes noninvasive cancers, such as DCIS, where abnormal cells remain within the ducts or lobules. Stage I involves small tumors (≤2 cm) that have not reached lymph nodes or distant areas. Stage II includes larger tumors (2–5 cm) or those that have spread to a limited number of nearby lymph nodes but not too distant organs. Stage III is considered locally advanced, with larger tumors (>5 cm) or significant spread to lymph nodes or surrounding tissues, but no distant metastasis. Stage IV, known as metastatic breast cancer, signifies that the cancer has spread to distant organs like the bones, liver, lungs, or brain. Understanding these stages is crucial for determining the most effective treatment and predicting patient outcomes [4].

Figure 1.

Stages of breast cancer.

Mammography remains the gold standard for BC diagnosis, but it has limitations, with more than 20% of cases going undetected. In instances where mammography results are inconclusive, ultrasonography and magnetic resonance imaging (MRI) [5] are employed as supplementary diagnostic tools. Once BC metastasizes, it spreads through the lymphatic and circulatory systems to other organs, significantly complicating treatment and increasing mortality rates. Managing metastatic BC presents a formidable challenge due to the presence of distinct microenvironments at metastatic sites [6]. Traditional treatment approaches include surgery, chemotherapy, and radiotherapy. The introduction of hormonal and targeted therapies has significantly improved survival rates and now plays a crucial role in BC management alongside conventional treatments [7].

Currently, BC treatment relies on surgery, hormonal therapy, and targeted therapy. While these strategies have improved survival rates, they come with significant limitations. Surgery is often ineffective in metastatic cases, chemotherapy and radiotherapy can cause severe side effects and lead to drug resistance, and even targeted therapies are not always effective due to variations in patient response. Moreover, chemotherapy drugs are systemically distributed, leading to off-target toxicities that affect healthy tissues. These challenges highlight the urgent need for more precise, effective, and less toxic therapeutic approaches [7]. To address these limitations, researchers have increasingly turned to innovative solutions such as nontherapeutic strategies and precision medicine. Over the past few decades, nanotechnology has transformed cancer treatment by providing more targeted drug delivery methods, as shown in Figure 2. Nanoparticles (NPs) can exploit differences between healthy and cancerous cells to deliver drugs directly to tumors, enhancing therapeutic effects while reducing systemic toxicity. Various nanocarriers, including polymeric nanoparticles, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), have been explored for BC therapy. While these systems have shown promise, many still suffer from issues such as premature drug release, poor stability, and limited penetration into tumors [8].

Figure 2.

Nanoparticle-based therapies for breast cancer.

To address these limitations, hybrid nanoparticles (HNPs) such as Lipid – Polymer Hybrid Nanoparticles (LPHNPs) [9]. Lipid – Inorganic Hybrid Nanoparticles [10], Metal-Organic Framework (MOF) [11] Hybrid Nanoparticles, and Polymer-Polymer Hybrid Nanoparticles [12] have emerged as a next-generation nanocarrier system, combining the best features of multiple delivery platforms. Among various nanocarriers, lipid – polymer hybrid nanoparticles (LPHNPs) emerge as particularly promising for breast cancer therapy [13]. These systems consist of a polymeric core that encapsulates the drug, surrounded by a lipid shell. Lipid and polymer components work synergistically to enhance drug efficacy by improving stability, controlled release, and targeted delivery. Lipids provide a biocompatible and flexible matrix that can encapsulate both hydrophobic and hydrophilic drugs, protecting them from degradation and enhancing their absorption [14]. Polymers, on the other hand, contribute structural integrity and enable controlled or sustained drug release by responding to environmental triggers like pH or enzymes [15]. Together, these components improve the circulation time of the drug carrier, reduce premature clearance, and enable precise targeting of specific tissues or cells. This combination maximizes therapeutic effects while minimizing side effects, making the delivery system more efficient and effective [16]. This core-shell architecture offers several key benefits: high drug loading capacity, controlled and sustained drug release, enhanced tumor targeting, and reduced recognition by the immune system. The lipid layer mimics natural cell membranes, promoting efficient entry into cancer cells, while the robust polymeric core protects the drug from early degradation [17]. Additionally, LPHNPs can be customized for multifunctional applications, including the co-delivery of multiple drugs and real-time imaging, making them ideal candidates for theranostic use [9]. This review uniquely highlights the design, therapeutic potential, and translational challenges of LPHNPs in cancer therapy, integrating recent advances and critical analysis. It emphasizes the clinical barriers and formulation diversity. A comprehensive and structured literature search was carried out using three major scientific databases: PubMed, Scopus, and Web of Science. The search focused on identifying relevant peer-reviewed studies published within the time frame of 2 decades between 2009 to 2025. Specific keywords such as “Breast cancer,” “Polymeric Nanoparticle” lipid-polymeric-hybrid nanoparticles, “Type of polymeric Nanoparticle,” therapy for breast cancer treatment,” “Nanobin” and “formulation of polymeric-lipid hybrid nanoparticles.” For the present theoretical review, the inclusion criteria were used to ensure the selection of high-quality and pertinent literature related to lipid – polymer hybrid nanoparticles and their application in cancer therapy. The search strategy aimed to provide a thorough understanding of the topic by covering multidisciplinary research across these databases. This review will be beneficial for readers from the field of nanomedicine, precision medicine and the entire scientific community working on breast cancer-related translational medicine and patient outcomes.

1.1. Advantages and challenges of hybrid nanoparticles

LPHNPs bring several key advantages to BC treatment:

• Higher Drug Loading and Controlled Release – The core-shell design allows for efficient drug encapsulation and prolonged release, minimizing frequent dosing and side effects.

• Enhanced Targeting and Cellular Uptake – Functionalized lipid coatings can be modified with ligands, antibodies, or aptamers for more precise cancer cell targeting.

• Lower Toxicity and Improved Biocompatibility – The lipid shell reduces immune system recognition, enhancing circulation time and reducing off-target effects.

• Overcoming Drug Resistance – LPHNPs can bypass efflux pumps, increase intracellular drug accumulation and overcome chemotherapy resistance.

• Potential for Imaging and Theranostics – These nanoparticles can be loaded with imaging agents, allowing for real-time monitoring of drug delivery and tumor response [18–20]

However, some challenges remain:

• Complexity in Formulation – Precise control over size, stability, and drug loading is required for reproducibility and large-scale production.

• Potential Immune Response – Although lipid coatings improve biocompatibility, immune interactions must be carefully studied to avoid adverse reactions.

• Pharmacokinetics Considerations – The size and surface properties of LPHNPs influence how they distribute and clear from the body, affecting overall efficacy [18–20]

Several nanoparticle-based therapies are currently undergoing clinical trials or have already received regulatory approval. For instance, the gadolinium-chelated polysiloxane nanoparticle AGuIX® is in phase II trials (NCT03818386) for use in radiotherapy [21]. NanoTherm®, composed of superparamagnetic iron oxide nanoparticles, was approved by the European Medicines Agency (EMA) in 2013 for hyperthermia treatment [22]. Dextran-coated iron oxide nanoparticles, marketed as Sienna+®, are in phase IV trials (NCT02612870) for sentinel lymph node detection [23]. Additionally, Feraheme® (iron oxide nanoparticles coated with poly glucose sorbitol carboxymethyl ether) has been approved by the FDA since 2009 for iron replacement therapy [22].

As research progresses, LPHNPs hold great promise for revolutionizing BC treatment. Their ability to augment drug delivery, diminish side effects, and overcome drug resistance makes them strong candidates for future cancer therapies. However, moving from laboratory research to clinical applications requires addressing formulation challenges, scaling up production, and ensuring long-term safety. With continued innovation and collaboration between researchers, clinicians, and regulatory bodies, LPHNPs could play a transformative role in personalized breast cancer treatment [24].

2. Type of lipid polymeric nanoparticles

Lipid Polymer Nanoparticles, also known as Polymer Lipid Hybrid Nanoparticles or Lipid Polymer Hybrid Nanoparticles (LPHNs), are major distribution systems to liposomes and polymeric nanoparticles as they have dual lipid-mimicking characteristics of the cell membrane which means the lipid shell of LPHNs, composed of phospholipids such as lecithin or DSPE, closely resembles the phospholipid bilayer of cell membranes, enhancing biocompatibility, improving cellular uptake, and enabling fusion with biological membranes [25] Secondly, the polymer – lipid interface offers a secondary lipid-like behavior by forming a monolayer or a partially fluidic structure that provides dynamic interactions with serum proteins and cell surface receptors, similar to how lipoproteins and other membrane-associated lipid structures behave in the body [26]. This dual mimicry not only allows LPHNs to evade rapid clearance by the immune system (due to PEGylation or other stealth modifications) but also facilitates efficient drug delivery through membrane-like fusion or endocytosis pathways [27]. By combining these two lipid-like properties, LPHNs achieve enhanced biodistribution, cellular compatibility, and target-specific delivery, making them superior to traditional nanoparticles in mimicking the native transport mechanisms of lipid-based biological systems [28]. The polymeric core facilitates the structural advantages of the long-term controlled release of the drug. LPHNs are an engineered lipid shell and polymer core system, and different LPHNs are depicted in Figure 3. The effect of the shape and composition of LPHNs has also shown good results in terms of reticuloendothelial uptake. In one study, Li et. al. highlight the critical role of nanoparticle geometry in endothelial cell uptake and intracellular trafficking. By comparing spherical and elliptical disk-shaped carriers of various sizes (0.1–10 μm), it was found that carrier shape and size significantly affect targeting efficiency, circulation time, and endocytic pathway. Spheres were internalized more rapidly by endothelial cells, while disks exhibited longer circulation and improved targeting specificity. Larger, micron-sized carriers tended to remain in prelysosomal compartments longer, which benefited therapies like antioxidant enzyme delivery. In contrast, smaller carriers were better suited for delivery to lysosomes, enhancing treatments such as enzyme replacement for lysosomal storage diseases [29]. A unique type of nanoparticle was reported by Zhang et al. 2011. They developed an Erythrocyte membrane-coated nanoparticle, a multifunctional drug delivery vehicle containing the desirable characteristics of both polymeric nanoparticles and liposomes. The exclusivity of these NPs is that 1) the RBC membrane surrounds the bilayered lipid barrier, providing a microenvironment against diffusion, and they are also specific to blood group, as human erythrocytes contain numerous surface antigens and are classified into many different blood groups. In this regard, to optimize the NPs for long-circulating in the blood vessels, the prepared erythrocyte membrane-polymeric nanoparticles need to be cross-matched to patients’ blood, as in the case of blood transfusion. These NPs paved the path for personalized medicine, as the NPs can be custom-made to individual patients with little risk of immunogenicity by using their own RBC membranes as the particle coatings. Making them very versatile and unique as compared to other NPs [30]. The LPHNs can be categorized into five types.

Figure 3.

Type of lipid polymeric nanoparticles.

2.1. Polymer Core-Lipid Shell

Polymer core-lipid shell (PCLS) is a type of hybrid nanocarrier where a polymeric core, which provides structural stability and controlled drug release, is surrounded by a lipid shell. The Schematic representation of polymer core – lipid shell structures is shown in Figure 4 [30]. The lipid shell enhances biocompatibility, improves interaction with biological membranes, and can help evade immune recognition. This design combines the advantages of both polymers (durability and controlled release) and lipids (flexibility and biocompatibility), making it effective for delivering various drugs [31].

Figure 4.

Diagrammatic illustration of the polymer core-lipid shell structure with its key components: (a) Polymer core-lipid shell type featuring a lipid bilayer, and (b) Polymer core-lipid shell type with a lipid monolayer.

By modifying the polymer core composition, lipid shell thickness, and dosage, a sustained and controlled release of therapeutic agents can be achieved [32]. Beyond passive targeting, PCLS nanoparticles can be functionalized with aptamers [33], folic acid [34], transferrin [35], and single-chain tumor necrosis factors [36] to enhance tumor-specific targeting.

In one investigation, Fernandes et.al. developed a pH-sensitive lipid-polymer hybrid nanoparticle (LPNP) with a PLGA-based core and a TPGS-lipid shell to deliver doxorubicin (DOX) and alpha-tocopherol succinate (TS) for breast cancer therapy. The nanoparticles were carefully examined for their physicochemical characteristics and shape. The in vitro investigations showed that 4T1 breast cancer cells absorbed more DOX, had lower cell viability, and migrated less. The in vivo investigation on 4T1 tumor-bearing mice demonstrated that the LPNP-TS-DOX formulation inhibited tumor development more effectively. The enhanced treatment efficacy was ascribed to pH-responsive drug release, which resulted in increased DOX accumulation at the tumor site and the synergistic anticancer effects of TS. These data show the efficacy of LPNP-TS-DOX as a breast cancer medication delivery method [37]. In another study, Tran et. al. developed a chitosan-coated lipid nanocapsule (CLN) for improved hydrophobic artesunate (ART) delivery in cancer therapy. The negatively charged lipid nanoemulsion was generated using a modified hot homogenization process and subsequently coated with chitosan via electrostatic interaction, resulting in a positively charged system (+13.2 ± 0.87 mV) with a tiny particle size (160.9 ± 3.5 nm) and spherical shape. ART-CLN had great drug entrapment efficiency (95.49 ± 1.13%) and a prolonged release profile. Cellular uptake experiments using flow cytometry and confocal imaging indicated that ART-CLN was effectively internalized. Furthermore, ART-CLN demonstrated greater anticancer activity than free ART in breast cancer cell lines (MCF-7, MDA-MB-231). These findings suggest that encapsulating ART in a polymer-lipid hybrid nanocarrier increases its stability and therapeutic effectiveness [38]. In another study, Campos et. al. investigated the efficacy of polymer-coated lipid nanoparticles for paclitaxel delivery. The nanoparticles were synthesized using a modified high-pressure hot homogenization process. The SLN cores were coated layer-by-layer with chitosan and hyaluronan (HA) to improve targeting capabilities, allowing for selective engagement with HA receptors on MCF-7 breast cancer cells. The produced nanoparticles were nanoscale, stable, and negatively charged. The chitosan-HA-coated lipid nanoparticles showed better cellular uptake, targeted drug administration, and regulated release of PAX, which improved its chemotherapeutic effects. These findings indicate that prepared nanoparticles are prospective carriers in nano-oncology, providing a focused and effective method for combating multidrug-resistant cancer cells [39].

Lakshmi et. al. created polymeric aqueous core nanocapsules (ACNs) for the synergistic administration of vinorelbine bitartrate (VRL) and resveratrol (RES) in breast cancer therapy. The ideal VRL-to-RES ratios (1:1, 5:1, and 10:1) demonstrated the greatest synergy against MCF-7 cells. The polymeric ACNs were synthesized utilizing a double emulsion solvent evaporation process, resulting in a stable core-shell structure with a small size (150.2 ± 3.2 nm) and great encapsulation efficiency (80% for VRL, 99% for RES). The in vitro results showed that polymeric ACNs were five times more efficacious than free medicines while exhibiting lower toxicity. Preclinical investigations demonstrated considerable tumor volume decrease, confirming the efficacy of polymeric ACNs as a targeted chemotherapeutic carrier [40].

2.2. Polymeric caged Nanobins

Polymeric-caged nanobins (PCNs) represent a subclass of LPHNs, where polymers are either grafted onto or anchored to the surface of liposomes to enhance their stability. PCNs are formed by encapsulating a drug-loaded core inside a polymeric “cage” or shell, typical size range of 10–100 nm. This cage acts as a protective barrier, preventing premature drug release and improving stability. The polymeric cage can be engineered to respond to specific stimuli (like pH or enzymes) for triggered release at the target site. Nanobins typically have a rigid, protective polymer shell that ensures controlled delivery and enhanced drug retention [31].

Chemotherapeutic agents such as arsenic trioxide and platinum-based compounds have been widely employed in treating promyelocytic leukemia, multiple myelomas, and solid tumors. However, arsenic trioxide exhibits limited bioavailability at tumor sites [41], while cisplatin, frequently used for ovarian, bladder, testicular, and solid tumors, tends to bind with plasma and tissue proteins, leading to systemic toxicity and the development of resistance in tumor cells [42]. Numerous liposomal formulations of arsenic and cisplatin have been investigated to prolong their circulation time in the bloodstream by minimizing rapid uptake by the reticuloendothelial system (RES) and increasing drug accumulation in tumor cells. However, liposomal arsenic trioxide (As₂O₃) showed low drug encapsulation efficiency and poor serum stability, as neutral As(OH)₃ easily diffuses through the liposomal membrane at pH levels below 9. To overcome these challenges, a novel approach was developed, involving the encapsulation of cisplatin-loaded polymeric nanoparticles within liposomal vesicles, a system known as nanobins.

In a recent study, Lee et al. [43] developed polymer-caged nanobins containing [Ni(HAsO₃)] to boost pro-apoptotic effects using an ion-gradient-mediated method. Arsenic, recognized for its capacity to trigger apoptosis and block angiogenesis, has been extensively utilized in treating acute promyelocytic leukemia and solid tumors [44]. Nickel was added to enhance arsenic’s cytotoxic effects by lowering intracellular levels of glutathione and ascorbate, which normally protect cells from apoptosis by counteracting heavy metal toxicity. The liposomes were created using DPPC, DOPG, and cholesterol. The preparation process involved hydrating a dried liposomal film with a nickel acetate solution, followed by stirring to form multilamellar vesicles. The formulation underwent 10 freeze-thaw cycles and was extruded through polycarbonate membranes. Finally, aqueous arsenic trioxide was loaded into the nickel-containing liposomal vesicles. The outer lipid layer was modified with polyacrylic acid, which was then cross-linked using a diamine cross-linker to assemble the nano bin system.

In one study, Lee et al. investigated doxorubicin-loaded polymer-caged nanobins (PCNDXR) in a mouse model of triple-negative breast cancer (MDA-MB-231 xenograft). The polymer cage surrounding the drug payload provides robust protection and acts as a pH-sensitive trigger, releasing doxorubicin more effectively in the acidic environments typical of tumors and endosomes. By adjusting the degree of cross-linking in the polymer cage, researchers were able to modify the surface charge of the nanobins, which in turn influenced their circulation time in the bloodstream. The results showed that PCNDXR significantly inhibited tumor growth in vivo while demonstrating good tolerance and reduced toxicity compared to free doxorubicin. These findings highlight the potential of polymer-caged nanobins as a promising platform for targeted and safer cancer treatment [45]. In another study, Lee et. al. revealed the effective co-delivery of doxorubicin (DOX) and cisplatin (Pt) utilizing a polymer-caged nanobin (PCN) to improve the efficacy of combination chemotherapy. The developed PCN comprises a doxorubicin-loaded liposomal core surrounded by a pH-responsive polymer shell containing a cisplatin prodrug. In this study, a monodisperse cholesterol-terminated poly (acrylic acid) polymer was used, offering uniform size and structure for consistent biological performance. The cholesterol end-group enhances membrane interaction and cellular uptake, while the poly(acrylic acid) backbone allows functional modifications. These features make the polymer highly suitable for targeted drug delivery. This architecture allows for adjustable medication ratios and surface charge potentials, improving therapeutic efficacy. The Pt-PCN-DOX formulation enhances cytotoxicity against cancer cells at lower dosages, outperforming free drug combinations and individually nano-packaged medicines. These findings highlight polymer-caged nanobins as a promising technique for improving synergistic effects in combination cancer treatment [46,47] In another study, Lee et al. created modular PCNs with clickable designs for targeted medication delivery. Using liposomes as templates, PCNs were created by adding cholesterol-modified poly (acrylic acid) and crosslinking using an alkyne-functionalized diamine linker. This arrangement allows for the attachment of azide-modified targeted ligands via click chemistry. The PCNs are pH-responsive, enabling the regulated release of the encapsulated doxorubicin (DOX) under moderately acidic circumstances. After conjugation with azide-modified folate, the folate-targeted DOX-loaded PCNs (f-PCN DOX) showed considerably increased cytotoxicity against folate receptor (FR)-positive cancer cells (KB and OvCa432) while demonstrating reduced efficacy in FR-negative cells (MCF7). The f-PCN DOX formulation specifically targeted FR-overexpressing tumors and demonstrated up to 50-fold enhanced efficacy, indicating the promise of this technique for receptor-mediated, pH-triggered cancer treatment [48]. In another investigation, Cabeza and colleagues demonstrate the effectiveness of poly(ε-caprolactone) (PCL) nanoparticles (NPs) as a drug delivery method for doxorubicin (DOX) in breast and lung cancer therapy. DOX-loaded PCL NPs were synthesized utilizing a modified nanoprecipitation solvent evaporation process, which increased the drug’s anticancer efficacy while minimizing harm to healthy tissues, due to the PCL nanoparticles improving the targeted delivery of DOX to tumor cells due to their favorable physicochemical properties and biocompatibility, allowing for greater cellular uptake in cancer cells compared to free DOX. This increased uptake leads to higher drug concentrations inside tumor cells, boosting the drug’s cytotoxic effects and significantly lowering the required effective dose (reflected by the 98% decrease. The in vitro experiments showed that these nanoparticles greatly increased drug absorption and cytotoxicity in human and murine breast and lung cancer cell lines, with an IC₅₀ reduction of approximately 98% in E0771 breast cancer cells. The in vivo investigations in tumor xenograft models showed that DOX-loaded PCL NPs reduced tumor volume by approximately 36% compared to free DOX, without producing substantial weight loss in mice [49]. In another research, Hong et. al., demonstrate that the multifunctional PCN platform serves as an effective theranostic system by simultaneously delivering chemotherapy drugs and MRI contrast agents specifically to HER2-overexpressing cancer cells. When conjugated with the targeting ligand Herceptin, the nanocarrier (Her-GdIII-PCNDXR) exhibits significantly enhanced cellular uptake and acid-triggered drug release, leading to a 14-fold increase in cytotoxicity compared to non-targeted carriers. Additionally, Herceptin conjugation dramatically improves the uptake of GdIII contrast agents up to 120 times greater than free DOTA-GdIII, resulting in enhanced MRI imaging contrast. These results highlight the potential of the Herceptin-targeted PCN platform for precise, targeted therapy combined with improved diagnostic imaging of HER2-positive tumors [50].

2.3. Core-shell type hollow lipid polymer nanoparticles

Core-shell type hollow lipid polymer nanoparticles (CSTHLPNs) are a class of hybrid nanoparticles designed with a hollow inner core surrounded by alternating lipid and polymeric layers, with an additional outer lipid-PEG coating. This unique structure provides advantages in drug and gene delivery, particularly for small interfering RNA (siRNA), which faces significant barriers to clinical translation due to its polyionic and macromolecular nature. siRNA therapy holds promise for managing a wide range of diseases by silencing specific gene expressions. However, its clinical application is hindered by its inherent instability, rapid degradation by nucleases, and inability to cross cell membranes due to its hydrophilic and negatively charged characteristics. CSTHLPNs offer an innovative approach to overcoming these challenges by enabling sustained and efficient siRNA delivery while improving cellular uptake and stability [51]. The design of CSTHLPNs incorporates multiple functional layers to address these limitations. The inner core is composed of cationic lipids, providing a positively charged environment that enhances siRNA encapsulation and complexation through electrostatic interactions. Surrounding this core is a polymeric layer, typically composed of poly lactic-co-glycolic acid (PLGA), which facilitates sustained release of the encapsulated siRNA, ensuring prolonged gene silencing effects. The outer lipid layer, modified with PEG, enhances nanoparticle stability and extends circulation time by reducing opsonization and immune clearance. In addition to siRNA, CSTHLPNs are highly effective in delivering hydrophobic drugs, making them versatile carriers for co-delivery applications. Their multilayered architecture allows for precise control over release kinetics, targeting specificity, and intracellular trafficking. The surface of these nanoparticles can also be functionalized with targeting ligands, enhancing receptor-mediated endocytosis and intracellular delivery to specific cells or tissues [52]. The fabrication of CSTHLPNs is typically achieved through a modified double-emulsion method. This process involves forming a water-in-oil-in-water (W/O/W) emulsion, where the siRNA is encapsulated within the inner aqueous phase, followed by polymer and lipid deposition to form the structured layers [53]. Various formulation parameters influence the physicochemical properties and performance of CSTHLPNs, including the composition of the inner cationic lipid core, molecular weight and composition of the polymeric layer, PEG chain length, and overall nanoparticle size. Optimization of these parameters is critical for achieving efficient siRNA loading, stability, and controlled release. Studies have demonstrated that CSTHLPNs significantly enhance gene silencing efficacy by improving siRNA intracellular uptake and endosomal escape (Table 1) [61]. The incorporation of PEG and targeting ligands further enhances circulation time and specificity, making these nanoparticles a promising platform for RNA-based therapeutics [62].

Table 1.

Core-Shell Hollow Lipid-Polymer Nanoparticles: study, drug and key findings.

Study	Drug	Inference	Ref.
Core-shell-type lipid-polymer hybrid nanoparticles	Various therapeutic agents	Lipid-polymer hybrid nanoparticles (CSLPHNs) provide a robust drug delivery platform with enhanced stability, controlled release, and multiple drug entrapment possibilities.	[17]
Nanoparticles for the therapeutic delivery of non‑coding RNAs	Non-coding RNAs (miRNAs, siRNAs)	Lipid‑based nanoparticles improve the delivery efficiency of ncRNAs, reducing cytotoxicity and reversing chemotherapy resistance.	[54]
Core-shell Magnetic@Platinium-Metal organic framework/epirubicin nano-platforms	Epirubicin	Core-shell nanoparticles enhance drug penetration and therapeutic efficacy in triple-negative breast cancer treatment.	[55]
Nanoparticle-Based Taxanes for Breast Cancer Treatment	Paclitaxel, Docetaxel	Taxane-based nanoparticles improve solubility and targeted delivery, reducing side effects and enhancing treatment efficacy.	[56]
Hybrid Core-Shell Nanodrugs for Targeted Photodynamic Cancer Therapy	Photodynamic therapy agents	Hybrid inorganic-organic core-shell nanoparticles enable high drug loading, enhanced stability, and improved localization for photodynamic therapy.	[57]
Advances in polymeric core-shell nanocarriers for targeted delivery of chemotherapeutic drugs	Various chemotherapeutic drugs	Polymeric core-shell nanocarriers enhance drug stability, prolong circulation, and allow controlled release for improved treatment outcomes.	[58]
Lipid-based nanocarriers for breast cancer treatment	Various lipid-based nanocarriers	Lipid-based nanoparticles provide effective breast cancer treatment with improved biocompatibility and therapeutic efficacy.	[59]
Functional polymeric core-shell hybrid nanoparticles	Silibinin and Curcumin co-loaded NPs	Enhanced stability and mucus diffusion improved nanoparticle uptake, boosting oral bioavailability.	[60]

2.4. Cell membrane camouflaged polymeric nanoparticles

Cell membrane camouflaged polymeric nanoparticles (CMCPNs) represent an innovative nanocarrier system that integrates the advantages of both synthetic and biological materials. These nanoparticles are composed of an inner polymeric core, which provides structural integrity and controlled drug release, and an outer shell derived from natural cell membranes. The biomimetic nature of these nanoparticles enables them to evade immune detection, extend circulation time, and enhance targeted drug delivery [63]. The core of CMCPNs is typically constructed from biocompatible polymers such as PLGA, polycaprolactone, gelatin, polyacrylamide, and silicon-based nanoparticles. Additionally, other nanostructures, including mesoporous silica nanocapsules, liposomes, gold nanoparticles, and Fe₃O₄ nanoparticles, have been employed to enhance drug encapsulation efficiency and therapeutic potential [64]. The outer shell is derived from cell membranes obtained from various biological sources, such as red blood cells, white blood cells, platelets, and cancer cells. The choice of membrane type influences the functionality and targeting efficiency of the nanoparticles. For example, RBC-derived membranes confer immune evasion and prolonged circulation, whereas cancer cell membranes can facilitate homotypic targeting, allowing nanoparticles to preferentially accumulate in tumor tissues (Table 2) [85].

Table 2.

Summary of studies on cell membrane camouflaged polymeric nanoparticles.

Study	Drug	Inference	Ref.
Cancer-cell-biomimetic Upconversion Nanoparticles	Doxorubicin, Near-Infrared (NIR) triggered chemo-photodynamic therapy	Enhanced tumor targeting, immune evasion, and systemic cytotoxic T-cell response	[65]
Leukocyte/Platelet Hybrid Membrane-Camouflaged Nanoparticles	Doxorubicin, Photothermal therapy (PTT) & Photodynamic therapy (PDT)	Improved targeting, synergistic PTT/PDT effects, and tumor growth suppression	[66]
Platelet Membrane-Camouflaged Silver Nanoparticles	Platelet Membrane	Increased blood circulation time, enhanced tumor accumulation, and apoptosis induction	[67]
Effective Triple-Negative Breast Cancer Targeted Treatment	Doxorubicin, RBC membrane-coated nanoparticles	Efficient targeting of TNBC, immune evasion, and prolonged circulation	[68]
Cell Membrane-Cloaked Bioinspired Nanoparticles	Various cellular membrane-cloaked nanoparticles for site-specific delivery	Longer retention time, improved targeting, and potential in vaccine development	[69]
Erythrocyte Membrane-Camouflaged DNA-Functionalized Nanoparticles	Doxorubicin	Targeting tumors effectively, improving chemotherapy, and combining immunotherapy	[70]
Biomimetic Nanomedicine Coupled with Neoadjuvant Chemotherapy	Cerium oxide	Tumour microenvironment remodeling is effective in reducing metastasis	[71]
Camouflaged Hybrid Cancer Cell-Platelet Fusion Membrane Nanovesicles	Therapeutic microRNAs, Systemic delivery	Targeted delivery of microRNAs, increased sensitivity to chemotherapy	[72]
Hyaluronic Acid-Coated pH-sensitive Polymeric Nanoparticles	Embelin (EMB) and the TRAIL plasmid	Increases pro-apoptotic as well as damaging effects on TNBC cells	[73]
Injectable Hydrogels Incorporating Dual-Nanoparticles	IR780 and Doxorubicin	Superior chemo-photothermal therapy efficacy, improved drug release under NIR	[74]
Research Update on Cell Membrane Camouflaged Nanoparticles	NA	Cell membrane-camouflaged nanoparticles enhance tumor targeting, immune evasion, and drug delivery, offering promising advancements in cancer theranostics and therapy.	[75]
Chitosan-Raloxifene Nanoparticles Containing Doxorubicin	Doxorubicin and Raloxifene	Effective targeting via estrogen receptors, enhanced stability	[76]
Improving Cancer Immunotherapy via Cell Membrane-Camouflaged Nanoparticles	NA	By enhancing tumors aiming for immune defense, and the administration of drugs while lowering inaccurate toxicity, cell membrane-camouflaged nanoparticles improve chemotherapy for cancer.	[77]
Metal Nanoparticles for Photodynamic Therapy in Breast Cancer	NA	Metal nanoparticle-based photodynamic therapy enhances breast cancer treatment by improving photosensitizer stability, targeting, and cellular uptake, enabling synergistic therapeutic effects.	[78]
Bionic Nanoparticles Camouflaged with Macrophage Membranes	macrophage membrane (MM)-encapsulated pH-responsive zeolitic imidazolate framework-8 (ZIF-8)-loaded naringenin nanoparticles	Absorbs more efficiently by cells and increases cellular drug accumulation	[79]
Cancer Cell Membrane-Camouflaged Metal Complex	Ruthenium polypyridyl complex	Enhanced solubility, biodistribution, and intercellular penetration	[80]
iRGD-Modified RBC Membrane-Camouflaged Nanoparticles	Doxorubicin	Biomimetic iRGD-RM effectively targets TNBC, evades immune clearance, and enhances antitumour efficacy, offering a promising therapeutic strategy.	[68]
Chitosan-coated nanomedicine enables stimuli-responsive drug release for multimodal imaging-guided breast cancer chemotherapy.	Paclitaxel	In this study, nanoparticles enable targeted, stimuli-responsive drug release, multimodal imaging, and potent chemo/PTT treatment for metastatic breast cancer treatment.	[81]
RBC membrane camouflaged Prussian blue nanoparticles for gamabutolin loading and combined chemo/photothermal therapy of breast cancer	Gamabufotalin (CS-6)	This research shows nanoparticles enhance targeted CS-6 delivery, prolong circulation, evade immunity, and amplify photothermal therapy, enabling effective, side-effect-free cancer treatment.	[82]
Breast Cancer Cell Membrane Camouflaged Lipid Nanoparticles for Tumour-Targeted NIR-II Phototheranostics	IR1048	In this study, nanoparticles enhance IR1048 solubility, enable tumor-targeting, and achieve effective NIR-II photothermal treatment with excellent specificity and biosafety.	[83]
Camouflaged, activatable and therapeutic tandem bionanoreactors for breast cancer theranosis	Tamoxifen	Prevent Early Enzyme Leakage and Enable Effective Stealth Capabilities.	[84]

2.5. Monolithic hybrid system nanoparticles

The archeological parameter of monolithic hybrid systems, commonly referred to as mixed LPHNPs, possesses a distinctive architectural dimension wherein lipid molecules are randomly dispersed, forming a core suitable for the loading of hydrophobic drugs. This strategic combination of nanoparticulate systems functions as a colloidal vehicle for the encapsulation of hydrophobic pharmaceutical agents. Phospholipids play a crucial role in the hybrid structure, contributing to the formation of a carrier-like framework. These LPHNPs are capable of entrapping highly lipophilic drug molecules that would otherwise be unable to be encapsulated within a polymer matrix. Furthermore, the mixing ratios of lipid and polymer can be adjusted and optimized during the manufacturing process to mitigate systemic toxicity throughout the body [86]. In one study, Carrese et al. developed bioinspired hybrid nanoparticles using human serum albumin (HSA) as a carrier for Dox, designed to serve both therapeutic and diagnostic purposes in breast cancer. These nanoparticles showed enhanced uptake and deeper penetration into 3D breast cancer spheroids compared to normal breast cell spheroids. Confocal imaging revealed that doxorubicin initially accumulated in the cytoplasm and progressively moved into the nucleus over 24 hours, indicating time-dependent drug internalization. In cytotoxicity studies, the nanoparticles showed significant anti-tumor activity only at higher drug concentrations after prolonged exposure. However, when combined with photothermal laser irradiation, enhanced tumor cell killing was achieved even at lower doses and shorter exposure times. Additionally, the nanoparticles demonstrated strong photoacoustic signals that increased with concentration, highlighting their potential for imaging [87] In another study, Mansur et. al. developed multifunctional nanoplatforms, designed specifically to target and treat TNBC, a highly aggressive and treatment-resistant cancer type. The nanostructure integrates four key components: superparamagnetic iron oxide nanoparticles for inducing ferroptosis through Fenton-like catalytic activity and enabling magnetically induced hyperthermia; carboxymethyl cellulose as a biocompatible and water-soluble stabilizer; folic acid for targeting folate receptors that are overexpressed on TNBC cells; and doxorubicin as a chemotherapeutic agent. The combined system effectively targeted TNBC cells in vitro, leveraging three complementary mechanisms of action: ferroptosis, thermal destruction via magnetic fields, and DNA damage from doxorubicin. These synergistic effects resulted in significant cancer cell death while aiming to minimize harm to healthy tissues. The findings highlight the promise of such multimodal nanotherapeutics for overcoming resistance in difficult-to-treat breast cancers and advancing precision-targeted cancer therapies [88].

3. Method of preparation of lipid polymeric NPS

Several distinct methodologies have been employed in the formulation of lipid-polymeric hybrid nanoparticles (LPHNPs), utilizing different processing techniques. In single-step methods, the polymeric core is formed through the precipitation process, facilitated by homogenizing the aqueous and organic phases. This allows for self-assembly, where a single-layered lipid shell surrounds the core. Concurrently, PEGylated lipids systematically arrange themselves, with the lipid portion anchoring onto the polymeric surface while the PEG chains extend outward, enabling functional modifications [89,90].

Alternatively, the two-step method for LPHNP preparation involves an initial bilayer formation, ensuring strong adhesion between the lipid and polymeric components. However, this bilayer undergoes partial disintegration due to hydrophobic and van der Waals forces, along with electrostatic interactions. These interactions play a critical role in stabilizing the final composite, making the process thermodynamically favorable [91,92].

The major techniques used for LPHNP fabrication are outlined below (Table 3: Method of Preparation of Lipid Polymeric NPs), detailing the methods, polymers used, solvents, and preferred drug classes.

Table 3.

Method of preparation of lipid polymeric NPs.

Methods	Polymer Used	Solvent	Preferred Drug Class	Ref.
Emulsification solvent evaporation	lipoid 90 H, chitosan, Polyvinyl alcohol	Dichloromethane	BCS- 2 & 4	[93]
Single-step nanoprecipitation technique	Phospholipon 90 G, Poloxamer-188, Polycaprolactone	N, N-Dimethylformamide	BCS- 2 & 4	[94]
The single emulsion-solvent evaporation technique	PLGA, polyvinyl alcohol, phosphatidylcholine	Dichloromethane	BCS- 2 & 4	[95]
Molecular self-assembled method	Chitosan, lecithin	Chloroform	BCS-2	[96]
Emulsification solvent diffusion method	Cholesterol, Poloxamer 407	Dichloromethane and methanol	BCS-4	[97]

3.1. One-step method by conventional nanoprecipitation

Nanoprecipitation [98], known as a solvent-displacement method, is the most commonly used method to produce polymeric nanoparticles. In this method, firstly, the to-be-encapsulated substance, followed by polymers such as PLGA and PBAE, is dissolved in a water-miscible organic solvent, meanwhile, substance such as DSPE-PEG and DMPE-PEG, known as lipids, is dispersed in water. The most common organic solvents that are used in conventional nanoprecipitation methods are acetone and acetic acid. To form a homogeneous dispersion, the lipid solution needs to be heated in the temperature range from 65°C to 70°C before adding the polymer solution in a dropwise form. As the polymer solution is added to the aqueous lipid dispersion under continuous stirring, it will cause the polymer to precipitate into the form of nanoparticles.

Due to hydrophobic interactions [31], where the hydrophobic tail of the lipids is attached to the polymer core and the hydrophilic head sticks out to the external aqueous surrounding, the lipids will eventually self-assemble around the polymeric nanoparticles, resulting in the formation of LPNs. Then, the LPNs produced will be recovered by undergoing the process of centrifugation after the solvent is evaporated. For example, Zhang et al. [99] have been using lecithin or DSPE-PEG as a lipid and PLGA as a polymer to encapsulate docetaxel with a size of LPNs from 70 nm to 80 nm. Another example, Wang et al. [100] also has been using PLGA as a polymer material and lecithin, DMPE, DTPA, or DSPE-PEG as a lipid substance to encapsulate docetaxel with a size of 65 nm and zeta potential of 35 mV.

3.2. One-step method by emulsification-solvent-evaporation (ESE)

Another one-step method that is used to produce LPNs alongside the conventional nanoprecipitation method is the emulsification-solvent evaporation method. This method typically produces larger LPNs compared to the nanoprecipitation method. There are two types of ESE methods, which are single and double emulsification methods. The only difference between these two methods is the solubility possessed by the substance to be encapsulated, soluble in a water-immiscible solvent, or insoluble in any organic solvent. The substance that is soluble in a water-immiscible solvent will undergo a single emulsification method where the oil phase or water-immiscible solvent, which contains the polymer and the substance to be encapsulated, is added into an aqueous phase of lipid under constant stirring or ultrasonication. This is done to produce an oil-in-water emulsion (o/w).

The polymer core is formed after the oil phase is removed by the evaporation process, using heat and/or reduced pressure (using a rotary evaporator or vacuum system), causing the solvent to vaporize and leave behind solid nanoparticles [101]. The oil phase is important because it provides a medium in which the polymer, lipids, and drug are initially dissolved and uniformly mixed. This ensures intimate contact and proper encapsulation of the drug within the polymer matrix [102]. The LPNs are simultaneously formed due to hydrophobic interaction, in which the lipid self-assembles around the polymer core. Instead of adding the water-immiscible solvent, which contains the polymer and the substance to be encapsulated, into an aqueous phase of lipid, it will be less time-consuming if the lipid is dissolved together with the polymer and the substance to be encapsulated in the water-immiscible solvent [28]. On the other hand, when the substance to be encapsulated is insoluble in any organic solvents, a double ESE method is employed. In this method, the encapsulated substance is dissolved in the aqueous phase before being emulsified in an oil phase, which contains the polymer and the lipid. From water-in-oil-in-water emulsion (w/o/w), the water-in-oil emulsion (w/o) produced is emulsified again in an aqueous phase containing the lipid-PEG substance. After evaporation of the oil phase, the LPNs with a slightly different structure from the LPNs produced in a single ESE method are formed. The LPNs produced in the double ESE method consist of three layers [103], which are the inner lipid layer surrounding the aqueous hollow core, the middle polymer layer, and the outer lipid-PEG layer.

3.3. Conventional two-step method

The most popular and common method that is used in the early development stage of LPNs is the conventional two-step method. This method is performed by combining and mixing the preformed polymeric nanoparticles with the preformed lipid vesicles. The polymeric nanoparticles can be prepared by various methods such as emulsification-solvent-evaporation, nanoprecipitation, or high-pressure homogenization [104], meanwhile, the lipid vesicles can be prepared by hydrating the thin lipid film. With the presence of electrostatic interactions, lipid vesicles are adsorbed on the polymeric nanoparticles, which results in the mixed polymer-lipid suspension. Alternatively, instead of directly adding preformed lipid vesicles, the polymeric nanoparticles can also be added to a dried lipid film, which it is prepared by dissolving it in an organic solvent such as chloroform [105].

The mixed polymer-lipid suspension undergoes the process of ultrasonication or vortexing, which requires a temperature higher than the gel-to-liquid transition temperature of the lipid in order to form LPNs. For instance, Wang et al. [106] used PLGA as a polymer and FA-OQLCS, Chol, and PEG-OQLCS as lipids to encapsulate the doxorubicin and pEGFP DNA. Then, the LPNs produced will be centrifuged to separate them from the non-adsorbed lipid. Afterward, to approach the monodisperse size of LPNs, the after-separation from non-adsorbed lipid LPNs suspension will undergo either the extrusion process or the homogenization process. In the extrusion process, the LPNs size produced is in the range of the membrane’s pore size as the pure LPNs suspension is passed through a porous membrane. It was also used by Sengupta et al. [107] to prepare chemotherapeutic LPNs, which used PLGA as polymer and PC, Chol, and DSPE-PEG as lipids to encapsulate doxorubicin and combretastatin.

3.4. Non-conventional two-step method

Differing from the conventional two-step method, the non-conventional two-step method has employed methods such as spray drying and soft lithography particle molding to prepare the LPNs instead of mixing both preformed polymeric nanoparticles and preformed lipid vesicles. For instance, Hitzman et al. [108] mentioned that polymeric nanoparticles made from polylysine and polyglutamic acid were prepared by the spray drying process before being dispersed in a dichloromethane solution, which contains lipids such as cetyl alcohol and tripalmitin. Results in the formation of lipid-polymeric suspension, the suspension was later spray-dried to produce LPNs. Another technique used in non-conventional two-step methods, which are specifically employed for gene delivery [109], is a soft lithography particle molding technique known as Particle Replication in Non-Wetting Templates (PRINT).

In PRINT, the polymer, such as PLGA, was dissolved in an organic solvent along with the genetic material before casting it onto a polyethylene terephthalate (PET) sheet. The most common organic solvents used in this method are dimethyl sulfoxide (DMSO) or dimethyl formamide (DMF). Afterward, while in conformal contact with a PRINT mold, the PET sheet was heated, allowing the polymer to flow into the mold before solidifying due to exposure to ambient temperature, which results in polymeric nanoparticles or PLGA nanoparticles. Then, the mold was in conformal contact with a polyvinyl alcohol coated (PVA) PET sheet, which resulted in the harvest of polymeric nanoparticles from the mold. The LPNs are produced after the polymeric nanoparticles are released from the PVA-coated PET sheet by dissolving the PVA layer of the sheet using an aqueous solution of lipids, which also results in the removal of nanoparticles from the mold along with the formation of LPNs. Lastly, the LPNs produced after undergoing the process of freeze-drying were needle-shaped according to the precise length and zeta potential [110].

4. Application for cancer disease therapy

LPHNPs have proven to be efficient in the treatment of various carcinomas by facilitating the delivery of single drugs, drug combinations, or even multidrug therapy. The selection of an appropriate LPHNP formulation for cancer therapy depends largely on the nature of the drug molecule, whether it is hydrophilic, hydrophobic, or nucleic acid-based (such as siRNA or miRNA). To improve targeted drug delivery, LPHNPs can be functionalized with specific ligands that bind to cancer cells, leading to enhanced cellular uptake [111].

Due to their ability to encapsulate therapeutic agents and control drug release upon reaching tumor sites, LPHNPs have gained significant interest in both in vitro and in vivo cancer research. Several studies have demonstrated their effectiveness in treating cancers affecting the breast, lung, liver, prostate, skin, blood, bone, brain, and other organs. Additionally, their applications have extended to nasopharyngeal cancer [105].

In this context, Yu and Zhang developed lipid-polymer hybrid nanoparticles loaded with gefitinib and apatinib, which exhibited prolonged drug release, improved cellular uptake, and increased cytotoxicity, demonstrating promising therapeutic potential against this rare cancer type [112]. Furthermore, researchers have designed LPHNPs encapsulating conferone and methotrexate to enhance cancer cell internalization, induce apoptosis, and prolong the anticancer effect. In another study, Zeng et. al. developed LPHNPs with a polymeric core and lipid shell to co-deliver paclitaxel (PTX) and the drug resistance inhibitor celecoxib (CXB) for overcoming multidrug resistance (MDR) in cancer therapy. The system, PTX/CXB@LPNP, provided sustained drug release and significantly improved cytotoxicity in both drug-resistant (MCF-7/ADR) and nonresistant (HeLa) cancer cells compared to single-drug formulations. Enhanced apoptosis induction and reduced P-gp expression were observed, attributed to the inhibitory action of CXB. Additionally, the system lowered IL-10 levels, indicating the potential to reverse the immunosuppressive tumor microenvironment. These findings highlight the effectiveness of dual-drug LPNPs in overcoming MDR and improving chemotherapy outcomes [113]. In another study, Wong et. al. successfully developed LPHNPs for the effective delivery of the water-soluble anticancer drug doxorubicin hydrochloride (Dox), aiming to improve its efficacy against multidrug-resistant (MDR) breast cancer cells. The nanoparticles, formulated by complexing cationic Dox with an anionic polymer and lipid, showed high encapsulation efficiency (60–80%) and controlled drug release. Compared to free Dox, the Dox-loaded nanoparticles significantly increased cancer cell death by over eightfold in MDR cell lines, while exhibiting minimal toxicity from the carrier components. Additionally, the system enhanced cellular uptake and retention of Dox, maintaining its anticancer activity. These findings support the potential of this nanoparticle platform for improving chemotherapy effectiveness in drug-resistant cancers [114]. Similarly, Wong et. al. demonstrated that LPHNPs significantly improve the intracellular delivery and retention of Dox in cancer cells overexpressing P-glycoprotein (Pgp), a major factor in multidrug resistance. The Dox-loaded LPHNPs enhanced drug uptake and maintained higher intracellular levels after treatment compared to free Dox. Fluorescence imaging confirmed improved drug accumulation in the nucleus and lipid uptake, indicating efficient delivery. The mechanistic studies suggested that the nanoparticles enter cells primarily through phagocytosis, enabling Dox to partially bypass Pgp-mediated efflux. These results highlight PLNs as a promising strategy to overcome drug resistance in Pgp-overexpressing tumors by improving drug delivery and retention [115].

Some notable examples of these applications are further discussed in Table 4

Table 4.

Shows types of diseases and the type of polymeric NPs used.

Types of cancer/treatment	Drugs used for the treatment	Types of Lipid Polymeric Nanoparticles		Outcomes	Ref
		Polymers	Lipids
Breast Cancer	Salidroside	Poly-Lactic-co-Glycolic-Acid (PLGA), Polyethene Glycol (PEG) – PLGA-PEG-PLGA	Cholesterol and Lecithin	This study demonstrates that salidroside-loaded PLGA-PEG nanoparticles enhance breast cancer treatment by improving drug solubility, stability, and targeted delivery. The combination of cholesterol and lecithin optimizes nanoparticle formulation, promoting sustained release and increased therapeutic efficacy, potentially reducing tumor growth while minimizing systemic toxicity.	[116]
	Curcumin	2-Hydroxyethyl methacrylate + Choline formate ionic liquid	Stearic acid	Curcumin-loaded lipid-based nanoparticles effectively inhibit nitric oxide production and suppress cell adhesion molecules like ICAM-1 and MUC-1 within an hour, reducing vascular inflammation. This mechanism restricts circulating tumor cell migration, lowering metastasis risk and enhancing curcumin’s potential as an anti-cancer agent.	[117]
	2-Deoxy-5-azacytidine (DAC), doxorubicin	Poly-Lactic-co-Glycolic-Acid (PLGA)	Soybean lecithin, 1,2 - Distearoyl – sn – glycero − 3 - phosphorylethanolamine – Polyethelene Glycol (DSPE-PEG)	DAC reactivates tumor suppressor genes by inhibiting DNA methyltransferases and enhances cancer cell sensitivity to doxorubicin. Using nanoprecipitation, DAC and doxorubicin were encapsulated in PLGA-lecithin-DSPE-PEG nanoparticles, which synergistically suppressed MB231 breast cancer cell growth.	[118]
	Iron oxide nanoparticles, camptothecin	Poly-Lactic-co-Glycolic-Acid (PLGA)	Lecithin, 1,2 - Distearoyl – sn – glycero − 3 - phosphorylethanolamine – Polyethelene Glycol (DSPE-PEG)	Under normal conditions, the nanoparticles exhibited minimal drug release; however, RF stimulation significantly enhanced the release rate, resulting in 60% cell death.	[119]
Multi-Drug-Resistant Breast Cancer	Doxorubicin, Elacridar (GG918)	Hydrolysed Polymer Of Epoxidised Soybean Oil (HPESO)	Tristearin – stearic acid 30: 70 w/w	The combined delivery of DOX and Ela demonstrated significant inhibition of MCF-7/ADR tumor growth. These findings highlight the potential of acid-sensitive nanovesicles in enhancing antitumour effectiveness for multidrug-resistant breast cancer treatment.	[118]
	Doxorubicin, mitomycin C	Hydrolysed Polymer Of Epoxidised Soybean Oil (HPESO)	Myristic acid	A mitomycin C-phosphatidylcholine complex was encapsulated in a PLA shell and coated with DPPE, DSPE-PEG, and folate-conjugated DSPE-PEG for targeted drug delivery. These nanoparticles exhibited sustained release and enhanced tumor reduction (≥50%) in a xenograft mouse model.	[119]
Lung Cancer	Ginsenoside Rg3	Hyaluronic acid ceramide (HACE)	Egg PC, 1,2 - Distearoyl – sn – glycero − 3 - phosphorylethanolamine – Polyethelene Glycol (DSPE-PEG)	Ginsenoside Rg3 was encapsulated in Hyaluronic acid-ceramide nanoparticles, coated with Egg PC and DSPE-PEG, for targeted drug delivery. This formulation improved tumor accumulation, cellular uptake, and sustained release, enhancing the anti-cancer efficacy of Rg3 in tumor models.	[119]
Pancreatic Cancer	Salidroside	Poly-Lactic-co-Glycolic-Acid (PLGA), Polyethelene Glycol (PEG) – PLGA-PEG-PLGA	Cholesterol and Lecithin	Cholesterol synthesis is regulated by key enzymes, while transport and depletion influence cellular balance. Cholesterol-lowering agents reduce cancer cell growth, proliferation, and migration while promoting apoptosis, highlighting their potential anticancer effects.	[119]
Colon Cancer	Gold nanocrystals and Paclitaxel in polymer lipid bilayer. sorafenib and Cy7 NIR dye In the lipid shell	Poly-Lactic-co-Glycolic-Acid (PLGA)	DPPC, 1,2 - Distearoyl – sn – glycero − 3 - phosphorylethanolamine – Polyethelene Glycol (DSPE-PEG)	Gold nanoparticles show promising therapeutic effects in GI adenocarcinoma rodent studies, supporting their role in photothermal therapy and surgical complementation. However, standardization and reproducibility are needed before clinical application.	[120]
Liver Cancer	SiRNA (anti-GFP, anti-Luc, GAPDH	Poly-Lactic-co-Glycolic-Acid (PLGA)	Lecithin, Polycarbonate (PC), 1,2 - Distearoyl – sn – glycero − 3 - phosphorylethanolamine – Polyethelene Glycol (DSPE-PEG)	The delivery of GAPDH siRNA using LPNs to HepG2 hepatocytes achieved effective gene silencing in vitro, comparable to commercially available transfection agents. In vivo studies conducted on Balb/C nude mice demonstrated a 42–45% reduction in GAPDH expression. Additionally, the same research group explored siRNA delivery targeting prohibitin (PHB1), a gene associated with chemoresistance, cell proliferation, and apoptosis. The treatment significantly inhibited cell proliferation in vitro and reduced tumor burden by more than twofold in vivo.	[119]
Prostate Cancer	SiRNA (anti-luc, KIF11, etc.)	Polylactic Acid (PLA)	DC-Chol, 1,2 - Distearoyl – sn – glycero − 3 - phosphorylethanolamine – Polyethelene Glycol (DSPE-PEG)	The anti-cancer potential of these nanoparticles was evaluated in three prostate cancer cell lines – LNCaP, PC3, and DU145—where KIF11 silencing was achieved, resulting in decreased cell viability across all tested models.	[119]
	A10 RNA Apatamer, Docetaxel	Polylactic Acid (PLA)	DC-Chol, 1,2 - Distearoyl – sn – glycero − 3 - phosphorylethanolamine – Polyethelene Glycol (DSPE-PEG)	LPNs with A10 RNA aptamer were developed for targeted docetaxel delivery to PSMA-overexpressing prostate cancer cells, showing high drug-loading, sustained release (120 hours), stability, and enhanced specificity for cancer targeting.	[121]

4.1. 4.1 LPHNPs for breast cancer therapy

Breast cancer is a leading cause of cancer-related deaths among women worldwide, accounting for 10% of all cancers in women and ranking as the second most common non-skin cancer and fifth most deadly cancer overall. Breast cancer is categorized based on the presence or absence of receptors like estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor 2 (HER2). ERBB2-negative and triple-negative cancers lack all three of these markers [122]. Treatment strategies are tailored to these molecular subtypes. Current breast cancer treatment involves a multidisciplinary approach combining systemic and locoregional therapies, including radiation and surgery. Traditional treatments use BRCA mutation inhibitors, anti-HER2 therapy, and hormonal therapy, while newer approaches involve targeted therapy with ligands that bind to overexpressed receptors. Future breast cancer treatment aims to personalize medicine and reduce treatment intensity based on tumor biology and initial treatment results [123]. Lipid-polymer hybrid nanoparticles (LPHNPs) are being studied extensively for delivering chemotherapy drugs to treat breast cancer, and some examples are discussed, with a summary of Lipid-Polymer Hybrid Nanoparticles (LPHNPs) in Breast Cancer Therapy: Single, Dual Drug, Targeted, and Nucleic Acid Delivery Approaches in Table 5.

Table 5.

Summary of lipid-polymer hybrid nanoparticles (LPHNPs) for breast cancer therapy: single, dual drug, targeted, and nucleic acid delivery approaches.

Category	Drug(s)	Key Findings	Methodology	Lipid and polymer	Cell Line/Animal Model	Outcome	Ref
Single Drug Delivery	Docetaxel (DTX)	pH-dependent drug release, increased cytotoxicity, higher apoptosis, reduced tumor volume, improved bioavailability	Single-step nanoprecipitation method	DSPE-PEG (2000) NH2, PLGA	MDA-MB-231, Breast Cancer Model	Tumour reduction (31.9%), better than free DTX (69.85%)	[124]
	Doxorubicin (DOX)	Time and dose-dependent uptake, improved antiproliferative effect	Single-step nanoprecipitation method	PLGA, DSPE PEG 2000	MDA-MB-231, PC3	Less than 20% viable cells at 200 µg/mL compared to 35–40% with free DOX	[125]
	Gemcitabine (GEM)	Higher entrapment, improved internalization, lower IC50, enhanced bioavailability	Double emulsion solvent evaporation method	PLGA, PVA, PC, DSPE-PEG2000	Breast Cancer Cell Line, Sprague-Dawley Rats	IC50 (0.40–0.38 µM) vs. Gemko® (2.29–1.96 µM), 4.2 times longer half-life	[89]
	Methotrexate (MTX)	Higher drug release, dose-dependent antiproliferative effect	Single-step nanoprecipitation method	PLGA, Lipoid S-100, Lutrol® F-68,	MDA-MB-231, PC3	Greater inhibition compared to free MTX	[126]
	Sorafenib (SFN)	Controlled release, higher cytotoxicity via the microfluidic method	Microfluidic nanoprecipitation	PLGA, Lecithin, DSPE-PEG 2000	MDA-MB-231, PC3-MM2	Suppressed cell growth more than a bulk method	[127]
	Emodin	EMT inhibition, increased sensitivity to DOX and galunisertib	Nanoprecipitation	PLGA, DEPE-PEG 2000, Pluronic® F-68	MCF-7/ADR	Downregulation of EMT markers (N-cadherin, vimentin)	[128]
	DTX (pH-sensitive)	Enhanced release in acidic pH, reduced tumor burden	Single-step self-assembled nano-precipitation method	PLGA, DOPE, Oleic acid, egg PC, DSPE-PEG2000-NH2, Lutrol® F-87,	MDA-MB-231, MCF-7, Balb/c Mice	42% release at pH 5.5 (12 h), reduced tumor circulation in organs	[129]
	Camptothecin (CPT)	Magnetic field-responsive, controlled release	Single-step nanoprecipitation method	PLGA, soybean lecithin, DSPE-PEG,	MT2 Mouse Breast Cancer Cells	100% drug release in 48 h with RF stimulation	[130]
Targeted Drug Delivery	HCPT	cRGD-targeted LPHNPs, increased cellular uptake	Single emulsification-solvent evaporation method	PLGA, Egg lecithin, DSPE-PEG2000, DSPE, DMAP	MDA-MB-435s, MCF-7	IC50: 0.262 µM (MDA-MB-435s) vs. 0.723 µM (free CPT)	[131]
	Isoliquiritigenin (ISL)	iRGD-targeted LPHNPs, higher apoptosis, reduced tumor volume	single-step nanoprecipitation	DSPE-PEG2000, PLGA, Lecithin,	MCF-7, MDA-MB-231, 4T1 Mice	Tumour volume: 474 mm3 vs. control; reduced dose from 50 mg/kg/day to 25 mg/kg/day every two days	[132]
	Paclitaxel (PTX)	FA-targeted LPHNPs, sustained release, higher tumor inhibition	Thin-film hydration, ultrasonic dispersion	DSPE-PEG2000, (DSPE-PEG 2000- Folate	EMT6, L929, BALB/c Mice	Tumour inhibition: 65.78% vs. 48.38% (PTX-LPHNPs)	[133]
Dual Drug Delivery	DOX + GG918 (P-gp inhibitor)	Overcame MDR, enhanced DOX absorption, and lower IC50	Thin-film hydration, ultrasonic dispersion	Pluronic F-68, HPESO, stearic acid,	MDA-MB-435/LCC6/MDR1	IC50: 0.34 mg/mL (dual) vs. 0.94 mg/mL (free)	[134]
	PTX + miR-221/222 inhibitors	Improved cytotoxicity, pH-sensitive release	Modified emulsification solvent evaporation	Poly(D,Llactide-co-glycolide), Methoxy-poly(ethylene-glycol)-amine, DOPA,	MDA-MB-231	Cell viability reduced by 80% vs. 40% (PTX only)	[135]
	Mycophenolate (MPA) + Quercetin (QC)	Sustained release, higher cytotoxicity, increased survival rate	Nanoprecipitation	Pluronic® F-68, soya lecithin, DSPE-PEG2000, PLGA	MCF-7, Sprague-Dawley Rats	Tumour reduction (32.5%) vs. control (154.59%)	[136]
	Methotrexate (MTX) + Beta-Carotene (BC)	Fructose-targeted, enhanced apoptosis, reduced tumor volume	self-assembled nanoprecipitation technique	PLA, stearyl amine (SA), DMBA, DPPH, DSPE-PEG3000, Gelucire® 50/13, Pluronic® F-127	MCF-7, Wistar Rats	Residual tumor: 32% (Fu-BC-MTX) vs. 57.6% (plain BC+MTX)	[137]
	MTX + Aceclofenac (ACL)	Fucose-targeted, reduced tumor burden, MMP-1 suppression	Nanoprecipitation Single-step self-assembled	S100, Polycaprolactone, DMBA, stearyl amine, DSPE-PEG (2000)-NH 2, stearoyl polyoxyl-32 glyceride, Kolliphor P407, l-fucose	MCF-7, MDA-MB-231, Breast Cancer Model	Residual tumor: 19.54% (Fucose-MTX-ACL) vs. 33.73% (MTX-ACL)	[138]
	DOX + All-trans Retinoic Acid (ATRA)	Hypoxia-sensitive release, reduced resistance, improved metastasis inhibition	Single emulsion method	PLGA, PEG-DSPE	4T1, Tumoursphere Cells	Combination index: 0.69; reduced metastasis	[139]
	Isoliquiritigenin (ISL)	Zein-phosphatidylcholine hybrid, improved loading, enhanced biocompatibility	Ethanol injection followed by the conventional two-step	Soybean phospholipid, Cholesterol, Zein, Lecithin,	Triple Negative Breast Cancer	Effective in vitro and in vivo	[140]
Nucleic Acid Delivery	siRNA (Plk1)	Gene silencing (35.3%), reduced expression by 65%	Single-step nanoprecipitation method	cationic lipid BHEM-Chol, mPEG 5k-PLA 25k, homopolymer PLA 30k, mixture of mPEG-PLA and PLA	BT747, Breast Cancer Model	In vivo Plk1 gene silencing by 65%	[141]
	siRNA (IGF-1 R)	Downregulation of IGF-1 R, higher viability than lipid NPs	modified nanoprecipitation method	L, D-Lactide, SnOct2, cationic lipid DDAB, Dihydroxy-terminated PEG,	MCF-7	IGF-1 R downregulation (p < 0.01)	[142]
	siRNA + Lycopene	Dual delivery, cell cycle arrest, downregulation of IGF-1 R	nanoprecipitation method	Methoxypoly, Sn (Oct)2, DDAB lipid,	Breast Cancer Cells	Cell cycle arrest (G1 phase with lycopene)	[143]

4.2. Recent advancement

Recent advancements in LPHNs for breast cancer treatment focus on targeted drug delivery, controlled release, and overcoming multidrug resistance [144]. Recently, researchers have concentrated on developing pH/redox-responsive systems, HER2 or folate receptor-targeted LPHNs, and the co-delivery of chemotherapeutics with siRNA or immune modulators [145]. These hybrid systems offer enhanced therapeutic efficacy, reduced systemic toxicity, and improved bioavailability in preclinical models.

4.3. pH-responsive systems

LPHNs are designed to release drugs in response to tumor-specific enzymes such as matrix metalloproteinases (MMPs), which are overexpressed in breast cancer. These systems incorporate enzyme-cleavable linkers or coatings that degrade in the tumor microenvironment, enabling site-specific drug release. This approach enhances targeting, minimizes systemic toxicity, and improves therapeutic efficacy. In one study, Men et al. developed dual pH/redox-responsive lipid-polymer hybrid nanoparticles (LPNPs) using amphiphilic poly(β-amino esters) grafted with disulfide-linked poly(ethylene glycol) methyl ether (PBAE-ss-mPEG) and PEGylated lipids. The optimized PEGylated lipid modification enhanced the nanoparticles’ stability, drug-loading efficiency, and cellular uptake. Characterisation confirmed pH sensitivity with a pKb of 6.55, while redox responsiveness was evident from morphological changes under reducing conditions. In vitro studies demonstrated controlled doxorubicin release in acidic and reductive environments, minimal cytotoxicity of blank carriers, and superior anticancer efficacy of DOX-loaded LPNPs compared to free DOX. These findings suggest that the engineered LPNPs are promising candidates for targeted and stimuli-responsive cancer therapy [146]. In another study, Zhang et al. developed a novel pH-responsive core-shell lipid-polymer nanoparticle system (FA/PBAE/DTX-NPs) for targeted delivery of docetaxel to breast cancer cells. The nanoparticles consist of a poly (β-amino ester) (PBAE) polymer core and a lipid shell modified with DSPE-PEG2000 and folic acid for tumor targeting. These nanoparticles demonstrated uniform size, good physical stability, and pH-triggered drug-release behavior. The PBAE core facilitated endosomal escape through the proton sponge effect, thus enhancing intracellular drug delivery. The in vitro tests showed minimal toxicity from blank nanoparticles and significant cytotoxicity from drug-loaded ones against 4T1 cells. The in vivo results confirmed effective tumor targeting, strong antitumour activity, and low systemic toxicity, indicating the potential of FA/PBAE/DTX-NPs as an efficient and safe nanocarrier for breast cancer chemotherapy [147]. In another research, Narwade et al. developed a targeted LPHNP system for the co-delivery of paclitaxel (PTX) and tamoxifen (TMF) to treat TNBC. By functionalizing the nanoparticles with an αvβ3 integrin-specific aptamer, enhanced targeting and cellular uptake in TNBC cells were achieved. The aptamer-conjugated LPHNPs showed significantly greater cytotoxicity and apoptosis induction in both 2D and 3D TNBC cell models compared to non-targeted formulations and free drug combinations. The co-delivery of PTX and TMF via targeted LPHNPs led to superior anti-cancer activity, highlighting the advantage of combination therapy and targeted delivery. These findings suggest that αvβ3 aptamer-functionalized LPHNPs carrying PTX and TMF offer a promising strategy for effective TNBC treatment [148]. Sarma et al. successfully developed chitosan-coated, pH-sensitive LPHNPs for the co-delivery of curcumin (CUR) and paclitaxel (PTX) in breast cancer therapy. The nanoparticles, prepared using a nanoprecipitation method, exhibited optimal particle size, low polydispersity, high drug entrapment efficiency, and controlled release behavior under acidic tumor-like conditions. In vitro studies confirmed significantly enhanced cytotoxicity of the nanoformulated drugs compared to their free forms. Pharmacokinetic evaluations in rats demonstrated a notable increase in bioavailability and half-life for both drugs, indicating improved systemic retention. Overall, the chitosan-coated LPHNPs offer a promising platform for targeted and sustained delivery of chemotherapeutic agents in breast cancer treatment [149]. Tahir et al. developed LPHNPs capable of co-delivering both hydrophilic doxorubicin hydrochloride (DOX) and lipophilic doxorubicin base using a one-step modified nanoprecipitation method. The nanoparticles, composed of PLGA, lecithin, and DSPE-PEG2000, showed appropriate particle sizes and notable drug encapsulation efficiencies for both drug forms. Drug release studies revealed sustained release following Higuchi kinetics and Fickian diffusion, with the lipophilic DOX base exhibiting a slower release profile. The in vitro assessments demonstrated good biocompatibility, efficient cellular uptake, particularly for the DOX base, and enhanced anticancer effects compared to free drugs. These findings highlight LPHNPs as a promising platform for delivering both hydrophilic and lipophilic chemotherapeutic agents in cancer treatment [150].

4.4. Redox-responsive systems

LPHNPs are engineered to release anticancer drugs in response to elevated intracellular glutathione (GSH) levels found in breast cancer cells. These systems incorporate disulfide linkages that are cleaved in reductive environments, enabling targeted and controlled drug release. This approach enhances therapeutic precision, reduces off- target toxicity, and improves treatment outcomes in breast cancer therapy. In one study, Demirel et al. developed multifunctional magnetic lipid- polymer hybrid nanoparticles (FA- MHNPS) with a core- shell structure designed for targeted and stimuli- responsive delivery of doxorubicin (DOX) to breast cancer cells. The nanoparticles incorporate a folic acid- conjugated polymer for cancer cell targeting and a biocompatible shell that responds to acidic pH and high glutathione (GSH) levels typical of the tumor microenvironment. The FA- MHNPS demonstrated efficient DOX release under endolysosomal conditions, enhanced cellular uptake, and greater cytotoxicity and apoptosis induction compared to non- targeted nanoparticles. These findings highlight the potential of dual pH/redox- responsive FA- MHNPS as an effective platform for controlled and targeted breast cancer therapy [151]. In another study, Wu et al. developed aptamer- decorated lipid- polymer hybrid nanoparticles (APT- Dtxp/DDP- LPHNS) for the co- delivery of a redox- sensitive docetaxel prodrug (DTXp) and cisplatin (DDP) aimed at treating non- small cell lung cancer (NSCLC). The nanoparticles demonstrated an optimal size and surface charge, resulting in enhanced cellular uptake and significantly increased cytotoxicity compared to non- targeted and single- drug formulations. The combination of DTXp and DDP within the targeted nanoparticles produced a synergistic antitumor effect, leading to substantial tumor growth inhibition in NSCLC mouse models. These findings suggest that aptamer- modified LPHNs offer a promising strategy for improving lung cancer therapy by effectively overcoming drug resistance and enhancing treatment efficacy [152]. Additionally, Wu and colleagues developed folate- targeted, reduction- sensitive lipid- polymer hybrid nanoparticles (FLPNPs) for the targeted delivery of doxorubicin (DOX). These nanoparticles feature a PLGA core, a lecithin monolayer, and a reduction- responsive PEG- based shell conjugated with folic acid for tumor targeting. FLPNPs demonstrated excellent size stability under normal conditions but rapidly disassembled in a reductive environment mimicking a cancer cell, enabling faster drug release. In vitro assays showed enhanced cellular uptake and greater cytotoxicity against cancer cells compared to non- targeted or non- responsive controls. In vivo studies further confirmed that FLPNPs effectively accumulated in tumors, significantly inhibited tumor growth, and improved drug biodistribution, indicating their potential as a stable, controllable, and tumor- targeted anticancer delivery system [153].

4.5. Enzyme-responsive systems

LPHNPs are emerging as a promising strategy for targeted breast cancer therapy. These systems are designed to release anticancer drugs in response to enzymes overexpressed in the tumor microenvironment, such as matrix metalloproteinases (MMPs) or cathepsins [154]. By incorporating enzyme-cleavable linkers or shells into the nanoparticle structure, LPHNPs enable site-specific drug release, minimizing off-target toxicity. This approach enhances therapeutic efficacy and reduces systemic side effects, offering a smart, tumor-selective platform for controlled drug delivery in breast cancer treatment. In one study, Tang et. al developed a novel LPHNP designed to enhance the combined effectiveness of photothermal therapy (PTT) and chemotherapy for cancer treatment. The system co-delivers indocyanine green (ICG) and dichloroacetate (DCA), which are anchored to a polyethyleneimine (PEI) core, allowing for high drug loading and enzyme-responsive release in the tumor microenvironment. Encapsulation with lecithin and DSPE-PEG2000 improves the nanoparticles’ circulation time and reduces systemic toxicity. The LPHNP nanosystem demonstrated excellent stability, tumor-targeting ability, and therapeutic efficacy, significantly inhibiting tumor growth while minimizing harm to healthy tissues, highlighting its promise as a multifunctional platform for cancer therapy [155].

4.6. Patents

Despite their therapeutic promise, the clinical translation of LPHNPs remains limited due to several key challenges. One major hurdle is the complexity of their design, which combines both lipid and polymer components, making it difficult to ensure consistency and reproducibility in large-scale production. Regulatory approval also poses a significant barrier, as current frameworks are not fully adapted to hybrid nanocarriers, requiring extensive safety, pharmacokinetic, and stability evaluations. Moreover, the lack of standardized manufacturing protocols makes scalability and cost-effective production difficult, further hindering commercial viability. Addressing these issues through improved regulatory guidance, scalable fabrication methods, and robust quality control measures is essential to advance LPHNPs from the lab to clinical use [13,156]. Several patents have been filed addressing the challenges of breast cancer treatment, particularly in overcoming drug resistance, enhancing targeted drug delivery, and leveraging immunotherapy. Table 6 outlines a selection of recent patents, highlighting their therapeutic mechanisms and potential clinical applications.

Table 6.

The list of patents shows the breast cancer treatment.

No.	Patent No.	Details	References
1.	US 11,633,382 B2	The invention demonstrates that ER-negative breast cancers can be treated with anti-estrogen therapy when combined with anti-PDGF-CC antibody treatment. This combined approach could serve as an adjuvant treatment, for instance, to lower the risk of breast cancer recurrence after surgical removal of the primary tumor.	[157]
2.	CN 114,601,844 A	The Hsp70 inhibitor, specifically Apoptole or VER-155008, was utilized to counteract drug resistance in breast cancer cells caused by the overexpression of DNAJC12 during chemotherapy. Additionally, it promoted ferroptosis in breast cancer cells. By employing the Hsp70 inhibitor, the invention effectively reverses chemotherapy-induced drug resistance linked to DNAJC12 overexpression and enhances ferroptosis, thereby improving the efficacy of chemotherapeutic drugs and benefiting patients.	[158]
3.	CN 108,864,255 A	The invention reveals that a polypeptide was specifically designed to bind to breast cancer stem cells, and its application is in the preparation of breast cancer treatment medications. The amino acid sequence of this polypeptide is identified as SEQ ID NO.1. This polypeptide can be utilized in the development of therapeutic drugs for breast cancer. When coupled or bonded with medications or nanomaterials, the polypeptide enables targeted recognition, diagnosis, and treatment of breast cancer.	[159]
4.	WO 2023/201429 A1	The present application used a combination of homoharringtonine and paclitaxel in treating breast cancer, including triple-negative breast cancer.	[160]
5.	KR 20,190,106,123 A	Administering the breast cancer treatment agent alongside the Lonicera caerulea fruit extract can significantly enhance the agent’s effectiveness in alleviating breast cancer symptoms. Additionally, this combination offers the benefit of preventing and reducing various side effects associated with the use of the breast cancer treatment agent.	[161]
6.	CN 111,500,717 A	The application of a quantitative reagent for 5-hydroxymethylated cytosine in the development of a diagnostic device. This device is designed for one or more of the following purposes: predicting the metastatic potential of breast cancer, forecasting lymph node metastasis in breast cancer, prognosis of metastatic breast cancer, evaluating the effectiveness of treatment for metastatic breast cancer, and assessing the sensitivity of a metastatic breast cancer patient to therapy.	[162]
7.	CN 114,601,836 A	The invention discloses the use of an AKT inhibitor for treating breast cancer, falling within the pharmaceutical technology field. It addresses the issue of widespread chemotherapy drug resistance in breast cancer treatment. The AKT inhibitor, specifically (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7 H-pyrrolo[2,3-d] pyrimidin-4-yl) piperidine-4-carboxamide, known as Capivasertib, is employed to treat breast cancer. This inhibitor helps reverse drug resistance in breast cancer cells caused by the overexpression of DNAJC12 during chemotherapy and promotes ferroptosis in these cells. By using the AKT inhibitor, the invention effectively counteracts chemotherapy-induced drug resistance linked to DNAJC12 overexpression and enhances ferroptosis, thereby improving the efficacy of chemotherapeutic drugs and benefiting patients.	[163]
8.	US 2017/0209407 A1	The treatment involves administering a therapeutically effective amount of a selective androgen receptor modulator (SARM) compound to the subject.	[164]
9.	KR 20,190,136,976 A	A composition containing a 2,3,5-substituted thiophene compound demonstrated strong proliferation-inhibiting effects on breast cancers. It is particularly effective against triple-negative breast cancer and Herceptin-resistant breast cancer, which are highly lethal due to the lack of effective treatments. This composition can be effectively utilized for the prevention, alleviation, or treatment of breast cancer.	[165]
10	CN 116,139,161 A	The invention falls within the technical field of small-molecule targeted anti-tumor drugs, specifically focusing on the use of an HDAC (histone deacetylase) inhibitor in combination with an antimetabolite for breast cancer treatment. It provides a method for utilizing this combination in the preparation of a breast cancer treatment drug. The HDAC inhibitor and antimetabolite exhibit a strong synergistic effect, effectively treating breast cancer and offering an improved therapeutic option for patients.	[166]
11.	CN 115,372,611 A	The invention reveals the use of CD16+ fibroblasts in the diagnosis, prevention, and treatment of monoclonal antibody-resistant breast cancer. By analyzing the distinct distribution patterns of CD16+ fibroblasts in monoclonal antibody-sensitive and resistant breast cancer cells, these fibroblasts can serve as a biomarker for predicting and diagnosing resistance to breast cancer monoclonal antibodies and/or assessing treatment efficacy. This approach enables the timely identification of potential or existing monoclonal antibody resistance in individual breast cancer cases, allowing for prompt adjustments and the implementation of appropriate treatment strategies to extend patient survival. Additionally, by targeting the expression of VAV2 in tumor cells, the drug resistance induced by CD16+ fibroblasts can be effectively reversed. This enhances the responsiveness of breast cancer patients to monoclonal antibody therapy, improves sensitivity to such treatments, and boosts the effectiveness of anti-HER2 targeted therapies.	[167]
12.	CN 116,407,526 A	The invention discloses a breast cancer treatment drug, an adjuvant therapy drug, and an anti-tumor immune activation drug, along with the applications of trimethylamine oxide (TMAO) and its precursor, choline. TMAO and choline can activate anti-tumor immunity in triple-negative breast cancer, offering a novel approach to address the clinical challenge of poor immune treatment outcomes for this cancer type. This innovation enhances the efficacy of clinical immune therapies and reverses treatment resistance, providing a new strategy to improve the effectiveness of immune-based treatments.	[168]
13.	CN 108,034,725 A	The invention reveals the use of LINC02185 in the diagnosis and treatment of breast cancer. For the first time, it identifies a significant decrease in LINC02185 expression in breast cancer patients, supported by QPCR verification and ROC analysis. The results demonstrate that LINC02185 can serve as a diagnostic biomarker for breast cancer. By increasing LINC02185 expression, the proliferation, migration, and invasion of breast cancer cells can be effectively suppressed, positioning LINC02185 as a potential drug target for treating breast cancer and/or its metastasis.	[169]
14.	CN 116,327,944 A	The invention falls within the field of biological medicines and reveals the use of a miR-27a-3p inhibitor in at least one of the following applications: (1) developing a product to inhibit breast cancer cell proliferation; (2) creating a product to suppress breast cancer cell invasion; (3) formulating a product to prevent breast cancer cell migration; (4) preparing a product to inhibit breast cancer growth; (5) designing a product to block breast cancer metastasis; and (6) producing medicine for breast cancer treatment. The invention elucidates the mechanism by which miRNA recognizes gene targets to regulate transcription, offering a scientific foundation for discovering new breast cancer treatment targets and drugs. This breakthrough is expected to lead to the development of innovative therapies for breast cancer.	[170]
15.	CN 109,055,561 A	The invention is part of the biological technology field and specifically focuses on the use of lncRNA-AP003774.1 in the diagnosis and/or treatment of breast cancer. This lncRNA shows significant upregulation in breast cancer cells, making it useful for breast cancer screening. Additionally, the invention discovers that knocking out lncRNA-AP003774.1 effectively reduces the invasion, metastasis, and proliferation of breast cancer cells, highlighting its potential application in breast cancer therapy.	[171]
16.	CN 115,715,802 A	The invention reveals the use of a MyD88 inhibitor in developing drugs to treat breast cancer and reverse paclitaxel (PTX) resistance. It is confirmed that suppressing the MyD88 gene enhances a breast cancer patient’s sensitivity to paclitaxel, thereby improving treatment outcomes. Ursolic acid effectively inhibits MyD88 gene expression, and by modulating MyD88, PTX resistance in breast cancer can be reversed. This provides a valuable strategy for designing effective breast cancer treatment approaches.	[172]
17.	CN 118,416,199 A	This invention pertains to the pharmaceutical technology sector and seeks to introduce a new medical use of the oncolytic virus VG161 for treating breast cancer, as well as its combined application with paclitaxel (PTX) in breast cancer therapy. The fusion protein, which includes IL-12, IL-15, IL-15RA, and a PD-1/PD-L1 interaction-blocking fusion protein (TF-Fc), effectively suppresses breast cancer growth and reduces lung metastasis by promoting proinflammatory changes in the tumor microenvironment. This innovation is broadly applicable to first-line clinical breast cancer treatment and related technical fields, offering a novel therapeutic approach with significant clinical potential. The method holds substantial promise for widespread adoption and application.	[173]
18.	CN 114,410,780 A	The invention relates to the use of sodium glycochenodeoxycholate in the preparation of a drug for treating breast cancer, falling within the technical field of breast cancer therapy. This application reveals, for the first time, that sodium glycochenodeoxycholate exhibits significant biological activity in inhibiting the proliferation, metastasis, and invasion of breast cancer cells. It effectively suppresses the growth, spread, and invasion of breast cancer cells, thereby enhancing treatment outcomes and reducing the risks of breast cancer progression and metastasis.	[174]
19.	CN 111,518,903 A	The INPP5 B gene is utilized in the development of diagnostic and therapeutic products for breast cancer. Both the INPP5 B gene and its protein expression product serve as specific biomarkers for breast cancer diagnosis. Additionally, the INPP5 B gene and its expression product can function as a gene therapy tool for creating breast cancer treatment products, offering a novel approach to breast cancer management.	[175]
20.	CN 115,236,335 A	GPCPD1 was used as a molecular biomarker for diagnosing and treating triple-negative breast cancer, functioning as both a prognostic indicator and a potential therapeutic target. The invention offers an improved method for the diagnosis and prognostic assessment of triple-negative breast cancer, holding significant importance for research and treatment in this field. As a result, the associated kit possesses substantial practical application value.	[176]
21.	CN 113,533,727 A	The invention pertains to the use of arginine methyltransferase 3 (PRMT3) in the diagnosis and treatment of breast cancer. It has been demonstrated that PRMT3 expression is significantly higher in breast cancer tumor tissues compared to normal tissues, and elevated PRMT3 levels are strongly correlated with poor prognosis in breast cancer patients. Overexpression or inhibition of PRMT3 alters the stemness phenotype of breast cancer cells, affecting microsphere formation, tumourigenic potential, and resistance to conventional chemotherapy drugs. PRMT3 drives recurrence, metastasis, and treatment resistance by promoting epithelial-mesenchymal transition and enhancing breast cancer cell stemness, with its regulatory effects mediated through activation of the Wnt pathway. This invention offers a novel approach to the diagnosis, prognosis, and treatment of breast cancer.	[177]
22.	CN 114,410,780 A	The invention discloses the use of KIF4A in the diagnosis, prognosis, and treatment of breast cancer. KIF4A expression is significantly elevated in breast cancer cells, where it functions to inhibit cell proliferation, promote apoptosis, and disrupt the mitosis process. Additionally, high KIF4A expression in breast cancer patients is associated with increased immune infiltration levels, making KIF4A a valuable biomarker for diagnosis, therapy, and prognosis in breast cancer patients.	[174]
23.	CN 118,340,771 A	The invention reveals the use of Atorvastatin in the preparation of a drug for preventing and/or treating breast cancer, including its application as the sole active ingredient in such medications, as well as the use of atorvastatin calcium for the same purpose. The drug works by inhibiting HMGCR, thereby reducing blood levels of low-density lipoprotein cholesterol and regulating the progression of breast cancer. Through Mendelian randomization analysis, the invention provides strong evidence supporting the potential of Atorvastatin for developing related drugs to prevent and/or treat breast cancer. This discovery opens a new avenue for breast cancer treatment and prevention, offering the potential for more effective therapeutic options for patients.	[178]
24.	JP 2,017,214,360 A	The invention involves: assessing the expression of a specific gene in a sample taken from the subject; calculating a growth signature based on the gene’s expression in the sample; administering a breast cancer treatment that includes a taxane or taxane derivative if the sample is identified as having a low growth signature; and providing a breast cancer treatment without a taxane or taxane derivative if the sample does not exhibit a low growth signature. This approach enables personalized treatment of the subject’s breast cancer.	[179]

4.7. Challenges and limitations

LPHNPs represent a promising advancement in breast cancer therapy due to their combined advantages of liposomes and polymeric nanoparticles, several challenges and limitations still hinder their clinical translation [180]. One major challenge lies in the complexity of formulation, where achieving optimal stability, reproducibility, and uniformity in particle size and drug loading requires precise control over multiple parameters such as solvent selection, lipid-to-polymer ratio, and process conditions [181]. Additionally, large-scale manufacturing remains difficult due to the lack of scalable and cost-effective production techniques that ensure batch-to-batch consistency [182]. Another significant limitation is the potential for immunogenicity and off-target accumulation, which may cause unintended side effects or reduced efficacy. Despite efforts to enhance tumor-specific targeting using ligands or antibodies, the heterogeneity of tumor markers and the presence of biological barriers like the dense tumor stroma and multidrug resistance mechanisms can still limit effective drug delivery [183]. Furthermore, regulatory challenges and the need for extensive preclinical and clinical validation pose additional hurdles before these systems can be approved for widespread clinical use. Thus, while LPHNPs hold great potential, addressing these formulation, biological, and regulatory barriers is essential for their successful integration into breast cancer treatment regimens.

4.8. Future perspectives

LPHNPs hold immense promise for revolutionizing breast cancer therapy, offering a unique combination of the structural stability of polymers and the biocompatibility of lipids [184] The LPHNPs are expected to be further engineered for personalized and precision medicine approaches by incorporating patient-specific biomarkers and stimuli-responsive systems that release drugs selectively in the tumor microenvironment [185] Advanced targeting strategies using ligands such as antibodies, aptamers, or peptides will enhance the specificity of drug delivery to breast cancer subtypes, including triple-negative and HER2-positive cancers [186].

Additionally, LPHNPs may evolve into multifunctional theranostic platforms by integrating imaging agents alongside chemotherapeutics, enabling simultaneous diagnosis, real-time monitoring, and treatment [187]. Emerging areas such as gene therapy, immunomodulation, and CRISPR/Cas9 delivery could also benefit from LPHNP-based systems due to their versatility and ability to co-deliver multiple agents. Furthermore, advancements in scalable, reproducible manufacturing and regulatory standardization will be essential for translating LPHNP technologies from bench to bedside. Overall, LPNs represent a cutting-edge frontier with the potential to significantly improve treatment outcomes and quality of life for breast cancer patients.

5. Conclusion

Breast cancer is a leading cause of cancer-related deaths among women worldwide, accounting for 10% of all cancers in women and ranking as the second most common non-skin cancer and fifth most deadly cancer overall. Breast cancer is categorized based on the presence or absence of receptors like estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor 2 (HER2). ERBB2-negative and triple-negative cancers lack all three of these markers. Treatment strategies are tailored to these molecular subtypes. Current breast cancer treatment involves a multidisciplinary approach combining systemic and locoregional therapies, including radiation and surgery. Traditional treatments use BRCA mutation inhibitors, anti-HER2 therapy, and hormonal therapy, while newer approaches involve targeted therapy with ligands that bind to overexpressed receptors. Future breast cancer treatment aims to personalize medicine and reduce treatment intensity based on tumor biology and initial treatment results.

Research and development of biotechnology in medical applications are immersed in understanding the definition, advantages, and applications of nanotechnology toward the pharmaceutical industry. Nanotechnology, which includes nanoparticles, shows one of the potential services in drug delivery for efficient, safe, and stable platforms. Nanoparticles have been chosen as one of the drug delivery systems because of their versatility, where they can encapsulate several drugs in either the compound state, hydrophilic, hydrophobic, or in enzymes and genes. Nanoparticles containing amphipathic characteristics as the hydrophilic corona or surface, can help protect the drug to ensure that it slows the process of opsonization and prevents reticuloendothelial system (RES) clearance. The development of nanoparticles in drug delivery has provided an optimized drug delivery system as it brings excellent efficiency in targeting and prolonged drugs, which has become the most challenging in the pharmaceutical field.

Funding Statement

The authors would like to express their utmost gratitude and appreciation to Universiti Malaya for funding the research project form of Universiti Malaya - Grant Research Program - Research Cluster [CORG002-2025].

Article highlights

• The stages of breast cancer (0 to 5) are classified based on the tumor’s size, whether it has spread to lymph nodes, and if it has metastasized to distant organs.

• Polymeric nanoparticles, liposomes, SLNs, and NLCs have been explored for Breast Cancer therapy.

• Polymeric-caged nanobins (PCNs) are lipid nanoparticle polymers that are either grafted onto or anchored to the surface of liposomes to enhance their stability.

• Lipid hybrid nanoparticles can be functionalized with specific ligands that predicament to cancer cells, leading to enhanced cellular uptake.

• Several patents have been filed addressing the challenges of breast cancer treatment, particularly in overcoming drug resistance, enhancing targeted drug delivery, and leveraging immunotherapy.

Author contributions

Marwa Alawi- Original draft, editing, revision.

Ayah R Hilles- Original draft, reviewed, editing, revision, figures.

Mohit Kumar- Original draft, editing, revision, figures.

Mohd Danish Ansari⁴ - Original draft, reviewed, editing, revision, figures.

Syed Mahmood- Editing, revision, reviewed, supervision, conceptualization.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose