We use cookies to ensure our website works properly and to personalise your experience. Cookies policy
1Research Scholar, Department of Pharmacy, Lingayas Vidyapeeth University, Faridabad, India
2,4 Lecturer, Department of Pharmacy, Shri Krishna Pharmacy College, Rewa, India
3 Assistant Professor, Department of Pharmacy, Indubhai Patel College of Pharmacy and Research Centre, Dharmaj, Gujarat, India.
Dendrosomes are supramolecular, vesicular nanocarriers formed by encapsulating dendrimers, or dendrimer complexes with a therapeutic payload, within a liposomal lipid shell. First described by Sarbolouki and co-workers as a non-viral vector for gene transfer, the dendrosome concept has since expanded into a versatile platform for delivering small-molecule drugs, nucleic acids, and natural bioactive compounds. By combining the internal cavities and surface-functionalizable branching of dendrimers with the biocompatibility, amphiphilicity, and membrane-mimetic character of liposomes, dendrosomes mitigate the cationic-charge-associated cytotoxicity of dendrimers while improving the payload-carrying capacity and stability of conventional liposomes. This short communication summarizes the structural basis, synthesis strategies, and representative therapeutic applications of dendrosomes, with particular emphasis on dendrosomal nanocurcumin as the most extensively studied system, and on dendrosome-mediated gene and siRNA delivery. Key translational challenges, including batch-to-batch reproducibility, scale-up, long-term biosafety, and regulatory characterization, are discussed alongside emerging opportunities in ligand-mediated active targeting, stimuli-responsive release, and combination therapy.
The clinical translation of many potent therapeutic agents, particularly hydrophobic small molecules, peptides, and nucleic acids, is limited by poor aqueous solubility, rapid systemic clearance, off-target toxicity, and inefficient intracellular delivery [1,2]. Nanocarrier-based drug delivery systems have therefore been developed to improve pharmacokinetics, protect labile cargo, and, where possible, direct therapeutic agents preferentially toward diseased tissue [1,2]. Among the nanocarrier families explored for this purpose, dendrimers are hyperbranched, monodisperse macromolecules with a well-defined core-shell architecture, an interior capable of hosting guest molecules, and a densely functionalizable peripheral surface [1]. These properties make dendrimers attractive drug and gene carriers, but higher-generation cationic dendrimers, most notably polyamidoamine (PAMAM), can produce concentration- and generation-dependent membrane disruption and haemolytic toxicity that constrains their systemic use [1,3].
To address this limitation while retaining the structural advantages of dendrimers, Sarbolouki and colleagues introduced the term "dendrosome" in 2000 to describe a family of synthetic, hyperbranched, spherical, lipid-based vehicles for direct gene delivery into cultured cells and animal models [3]. Subsequent work refined the concept: dendrosomes are now generally understood as liposomal vesicles in which a dendrimer, or a dendrimer complexed with a nucleic acid or drug (dendriplex), is entrapped within or associated with a phospholipid bilayer shell [4]. This hybrid design shields the charged dendrimer surface from direct contact with biological membranes, lowering cytotoxicity and haemolysis while improving payload protection, circulation stability, and cellular uptake relative to either component used alone [3,4]. Given the accumulating evidence for their multifunctionality, this short communication provides a focused overview of dendrosome architecture, representative applications in cancer therapy and gene delivery, and the principal opportunities and barriers that will determine their clinical trajectory.
Table 1. Emergence and evolution of dendrosomes as nanocarriers.
|
Year |
Milestone / Development |
Reference |
|
2000 |
Term "dendrosome" coined; first-generation lipid-enveloped dendritic vehicles reported for direct gene transfection in cell culture and animal models. |
Sarbolouki et al. [3] |
|
2010 |
Dendrosome-encapsulated dendriplexes used to deliver siRNA against HPV E6/E7 oncogenes in cervical cancer cells, demonstrating reduced dendrimer-associated toxicity. |
Dutta et al. [13] |
|
2012 |
Dendrosomal curcumin formulation shown to suppress cancer cell proliferation in vitro and in vivo, establishing the platform for natural-compound delivery. |
Babaei et al. [6] |
|
2013 |
Conceptual framing of dendrosomes alongside vesosomes as modular, multicompartment lipid-based drug and gene delivery carriers. |
Paleos et al. [2] |
|
2015 |
Comprehensive formulation review describing amphiphilic oleic acid-PEG dendrosomes for curcumin encapsulation and improved bioavailability. |
Tahmasebi Birgani et al. [5] |
|
2016-2018 |
Mechanistic expansion: dendrosomal nanocurcumin combined with p53 re-expression, miRNA/epigenetic modulation, and chemotherapeutics (doxorubicin) in breast, liver, and brain cancer models. |
Keshavarz et al. [10]; Chamani et al. [12]; Mahjoub et al. [11]; Baghi et al. [9] |
|
2024 |
Continued mechanistic refinement showing dendrosomal curcumin-induced mitochondrial apoptosis and cell-cycle arrest in breast cancer cells. |
Abbasi et al. [8] |
2. Structural Architecture and Synthesis
Structurally, dendrosomes occupy an intermediate position between liposomes and dendrimers, combining an outer lipid bilayer, typically composed of phospholipids such as egg phosphatidylcholine or dioleoylphosphatidylethanolamine together with cholesterol, with an inner dendrimeric or dendriplex core [2,4]. Two broad architectural variants have been reported. In the first, exemplified by early gene-delivery dendrosomes, an amphiphilic dendron built from esterified oleic acid and polyethylene glycol chains self-assembles directly into a spherical, micellar, or polymersome-like structure capable of encapsulating hydrophobic drugs such as curcumin [5]. In the second, cationic dendrimer-nucleic acid dendriplexes are pre-formed and subsequently loaded into the aqueous core of conventional liposomes, yielding a lipid-enveloped dendriplex particle [4,6]. Both approaches converge on the same functional outcome: a lipid interface that improves biocompatibility and controls release, wrapped around a branched macromolecular core that provides high payload density and multivalent surface chemistry [2,4].
Preparation methods draw on established liposome technology, including thin-film hydration, solvent injection, and extrusion or sonication for size reduction, followed by characterization of particle size, zeta potential, polydispersity, and encapsulation efficiency [4,6]. Because the dendrimer core and lipid shell can each be independently modified, dendrosomes are inherently multifunctional platforms: the dendrimer periphery can be conjugated with targeting ligands, imaging tags, or stimuli-responsive linkers, while the lipid shell can be PEGylated to extend circulation time or functionalized with antibodies, peptides, or aptamers for active targeting [2,4].
Table 2. Principal structural components of a dendrosome and their functional roles.
|
Structural Component |
Composition / Description |
Functional Role |
|
Outer lipid bilayer shell |
Phospholipids (e.g., egg phosphatidylcholine, DOPE) combined with cholesterol, arranged as a liposome-like membrane. |
Confers biocompatibility and membrane-mimetic behavior; shields the charged dendrimer core; modulates release rate and reduces haemolytic toxicity. |
|
Inner dendrimer / dendriplex core |
Hyperbranched macromolecule (e.g., PAMAM) alone, or complexed with a drug, DNA, or siRNA payload. |
Provides high payload-carrying capacity, multivalent internal cavities, and condensation of nucleic acid cargo. |
|
Aqueous interlayer |
Hydrated space between the dendrimer core and the surrounding lipid bilayer. |
Houses the dendriplex; buffers direct contact between core and membrane; helps protect nucleic acid cargo from enzymatic degradation. |
|
Dendrimer peripheral groups |
Terminal amine, hydroxyl, or carboxyl functional groups on the dendrimer branches. |
Serve as conjugation sites for targeting ligands, fluorescent or imaging tags, and stimuli-responsive linkers. |
|
Lipid surface modifications (optional) |
PEG chains, antibodies, peptides, or aptamers grafted onto the outer lipid surface. |
Extend circulation half-life (stealth effect) and enable active, receptor-mediated targeting of diseased tissue. |
DOPE, dioleoylphosphatidylethanolamine; PAMAM, polyamidoamine; PEG, polyethylene glycol.
Table 3. Comparative structural and functional features of dendrimers, liposomes, and dendrosomes.
|
Feature |
Dendrimers |
Liposomes |
Dendrosomes |
|
Core architecture |
Solid hyperbranched macromolecule |
Hollow aqueous core within a lipid bilayer |
Dendrimer or dendriplex core enclosed within a lipid bilayer |
|
Payload capacity |
High (internal cavities and surface conjugation) |
Moderate (aqueous core and bilayer) |
High (dendrimer core plus bilayer/interlayer) |
|
Surface functionalization |
Extensive, via peripheral groups |
Moderate, via lipid head-group chemistry |
Extensive, on both dendrimer periphery and lipid surface |
|
Cytotoxicity / haemolysis |
Generation-dependent, can be significant for cationic types |
Generally low |
Reduced relative to unshielded cationic dendrimers |
|
Structural stability |
High (covalent branching) |
Moderate (susceptible to fusion/leakage) |
Enhanced by combining dendrimer rigidity with lipid flexibility |
|
Typical application focus |
Small-molecule and nucleic acid carriers |
Small-molecule, protein, and nucleic acid carriers |
Nucleic acid, siRNA, and hydrophobic natural-compound delivery |
3. Multifunctionality in Drug, Gene, and Bioactive Delivery
3.1 Anticancer applications: dendrosomal nanocurcumin
The most extensively investigated dendrosomal system in the literature is dendrosomal nanocurcumin (DNC), developed to overcome the very low aqueous solubility, rapid metabolism, and poor bioavailability that otherwise limit the anticancer potential of curcumin, a polyphenolic compound derived from Curcuma longa [5]. Encapsulation within a dendrosome markedly increases curcumin's apparent solubility and cellular uptake relative to the free compound [5]. DNC has demonstrated antiproliferative and pro-apoptotic activity across a range of malignant cell lines and animal tumor models, including breast, bladder, colon, hepatocellular, and glioblastoma cancers, generally acting through modulation of apoptosis-related genes and proteins such as Bax, Bcl-2, p53, and downstream survival pathways [5,7]. In breast cancer models, DNC has been shown to induce mitochondrial apoptosis and cell-cycle arrest at the SubG1 phase, accompanied by upregulation of pro-apoptotic factors (Bax, Noxa, PUMA, p21) and downregulation of anti-apoptotic and proliferative markers (Bcl-2, EZH2, Lnc-DANCR) [8]. DNC also acts synergistically with both exogenous tumor-suppressor gene expression and conventional chemotherapeutics: co-treatment with re-introduced p53 potentiates apoptosis in breast cancer and glioblastoma cells [9,10], while combination with doxorubicin enhances anticancer activity in metastatic breast cancer cells partly through modulation of the CXCR4/NF-κB/Smoothened signaling network [11]. In hepatocellular carcinoma cells, DNC treatment has additionally been linked to altered expression of the miR-34 family and DNA methyltransferases, suggesting an epigenetic dimension to its activity [12].
3.2 Gene and siRNA delivery
Beyond small-molecule delivery, dendrosomes retain strong utility as nucleic acid carriers, the application for which the platform was originally conceived [3]. Encapsulating a pre-formed dendrimer-siRNA dendriplex within a lipid shell mitigates the cytotoxicity associated with the high dendrimer generations required for effective nucleic acid condensation, while preserving gene-silencing performance. In a representative study, dendrosomal delivery of siRNA targeting the human papillomavirus E6 and E7 oncogenes achieved substantial knockdown in cervical cancer cells, with the lipid shell masking toxicity that was otherwise observed with the naked dendriplex [13]. More broadly, dendrosome-encapsulated dendriplexes have been explored as vectors for plasmid DNA and other genetic material, offering low haemolytic toxicity, favorable transfection efficiency, and good in vivo tolerance relative to unshielded cationic dendrimers or lipoplexes [4,6]. Multicompartment variants, in which liposomes encapsulate either smaller liposomes (vesosomes) or dendrimers (dendrosomes), have further been proposed as universal modular platforms capable of co-delivering combinations of drugs and genetic material with tunable release kinetics [4].
3.3 Vaccine and immunomodulatory applications
Dendrosomes have also been investigated as nano-sized adjuvants for genetic immunization, capitalizing on their capacity to protect entrapped nucleic acid from enzymatic degradation while promoting efficient cellular uptake by antigen-presenting cells [4,6]. Such applications extend the multifunctional scope of the platform beyond conventional chemotherapy into prophylactic and immunotherapeutic domains, although this area remains comparatively less developed than the oncology-focused literature.
4. Opportunities for Targeted Delivery
Several features position dendrosomes favorably for targeted drug delivery. First, their dual-component architecture allows independent, orthogonal functionalization of the lipid surface and the dendrimer periphery, enabling combinations of passive targeting (via PEGylation and enhanced permeability and retention in solid tumors) with active targeting (via ligand conjugation to receptors overexpressed on diseased cells) [2,4]. Second, the internal branching of the dendrimer core provides high payload capacity and the possibility of co-loading chemically dissimilar agents, for example a hydrophobic small molecule together with a nucleic acid, supporting rational combination therapy [4,11]. Third, because both dendrimers and liposomes are chemically tunable, dendrosomes are compatible with stimuli-responsive designs, such as pH-, redox-, or enzyme-sensitive linkers, that could enable triggered release within the tumor microenvironment or endosomal compartment. Finally, relative to unshielded high-generation dendrimers, the lipid envelope of dendrosomes measurably reduces haemolytic and cytotoxic liabilities, which is an important step toward systemic administration [3,4].
5. Challenges
Despite this promise, several obstacles must be resolved before dendrosomes can progress toward clinical use. Reproducible, scalable synthesis remains a central concern: multi-step assembly of dendrimer or dendriplex cores followed by lipid encapsulation introduces batch-to-batch variability in particle size, encapsulation efficiency, and surface charge that complicates good manufacturing practice-compliant production [2,4]. Comprehensive long-term toxicological and immunogenicity data, particularly for cationic dendrimer components and for repeated dosing regimens, are still limited relative to more established nanocarrier classes such as liposomes and polymeric nanoparticles [1,3]. Physicochemical characterization is similarly demanding, since dendrosomes possess a more complex, multicompartment architecture than single-component nanocarriers, requiring orthogonal analytical methods to confirm dendrimer encapsulation, payload location, and structural integrity during storage [4]. Regulatory pathways for such hybrid, multicomponent nanomedicines are not yet well established, and in vivo pharmacokinetic and biodistribution data, especially in large-animal and human studies, remain sparse compared with the extensive in vitro literature [1,2]. Cost and complexity of production relative to simpler liposomal formulations may also limit near-term commercial adoption.
FUTURE PERSPECTIVES
Future work should prioritize standardized, scalable manufacturing protocols and harmonized characterization criteria to enable meaningful comparison across studies. Systematic in vivo pharmacokinetic, biodistribution, and chronic toxicity studies are needed to translate the substantial in vitro anticancer and gene-silencing data into credible preclinical development candidates. Incorporation of active-targeting ligands and stimuli-responsive chemistries offers a route toward more precise, tumor- or tissue-selective delivery, while co-encapsulation strategies that pair dendrosomal nanocurcumin or other natural compounds with conventional chemotherapeutics may help address multidrug resistance through synergistic, multi-pathway mechanisms [5,11]. Expanding dendrosome research beyond oncology, into gene therapy, vaccination, and inflammatory or infectious disease applications, would also help clarify the general versatility of the platform. With coordinated attention to reproducibility, safety characterization, and regulatory alignment, dendrosomes are well positioned to mature from a promising laboratory-stage nanocarrier into a clinically viable multifunctional delivery platform.
CONCLUSION
Dendrosomes combine the payload capacity and surface tunability of dendrimers with the biocompatibility and membrane-mimetic properties of liposomes, yielding a multifunctional nanocarrier platform with demonstrated activity in anticancer drug delivery, gene and siRNA delivery, and genetic immunization. Dendrosomal nanocurcumin, in particular, illustrates how this hybrid design can substantially improve the solubility, cellular uptake, and therapeutic efficacy of a poorly bioavailable natural compound. Realizing the full clinical potential of dendrosomes will require sustained progress in reproducible synthesis, in vivo safety and pharmacokinetic characterization, and targeted delivery engineering.
REFERENCES
Vivek Gautam Kajal Mishra, Ayush Agrawal, Pritam Kushwaha, Dendrosomes as Emerging Multifunctional Nanocarriers for Targeted Drug Delivery: Opportunities, Challenges, and Future Perspectives a Short Communication, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 9, 2629-2636, https://doi.org/10.5281/zenodo.22895077
10.5281/zenodo.22895077