Liposomal Nanoparticulate Drug Delivery Systems: Engineering Membrane Destabilization for Precision Nanomedicine
核心洞察
Liposomal nanoparticulate drug delivery systems (LNDDSs) have evolved from passive carriers into sophisticated platforms capable of traversing biological barriers including the blood-tumor barrier, blood-brain barrier, and lymphatic transport barrier.
Recent advances focus on stimuli-responsive membrane destabilization strategies—pH, enzyme, redox, thermal, and ultrasound-triggered—to achieve spatiotemporally controlled drug release at target tissues.
Despite clinical successes like Doxil® and mRNA COVID-19 vaccines, delivery efficiency remains below 2% following intravenous or subcutaneous administration, highlighting persistent translational challenges.
Liposomal nanoparticulate drug delivery systems (LNDDSs), first described by Alec Bangham in the 1960s, have undergone a remarkable transformation from simple phospholipid bilayer vesicles into clinically validated, highly engineered nanomedicines. A comprehensive review published in the International Journal of Nanomedicine now examines the current and emerging strategies by which these systems are designed to selectively cross and destabilize biological barriers—a critical determinant of therapeutic success.
The review traces the clinical trajectory of LNDDSs from the landmark approval of Doxil® (liposomal doxorubicin) in 1995, which demonstrated improved pharmacokinetics and reduced systemic toxicity in oncology, through to the recent success of lipid nanoparticle-based mRNA vaccines such as Moderna's mRNA-1273 and Pfizer's BNT162b2. "Understanding and harnessing these mechanisms is now critical for developing next-generation liposomal nanomedicines capable of achieving selective, efficient, and clinically translational drug delivery systems," the authors state.
Traversing the Blood-Tumor Barrier
LNDDSs cross the blood-tumor barrier (BTB) primarily through two transport pathways: passive extravasation via the enhanced permeability and retention (EPR) effect, and active transport and retention (ATR) mechanisms, particularly receptor-mediated transcytosis. However, the EPR effect—long considered the "gold standard" for tumor-targeted nanomedicine—faces significant obstacles due to the pronounced heterogeneity of the BTB across tumor types and stages, together with dense extracellular matrix (ECM) and elevated interstitial fluid pressure.
To overcome these limitations, recent designs have focused on stimuli-responsive membrane destabilization. pH-sensitive LNDDSs exploit the acidic tumor microenvironment (pH 6.5–6.9), while enzyme-cleavable systems leverage aberrant expression of matrix metalloproteinases, β-galactosidase, and cathepsins. In one notable example, Liu et al. developed an MMP- and pH-dual responsive LNDDS in which an MMP-cleavable linker enabled extracellular release of a PD-L1 (搜索) inhibitor, while a pH-responsive polymer facilitated endosome escape—producing synergistic chemo-immunotherapy in B16F10 melanoma (搜索) mouse models.
Zhou et al. engineered a doxorubicin-loaded dendritic macromolecule encapsulated within pH-sensitive LNDDSs for co-delivery of an immunoadjuvant R848 and losartan. The combination promoted robust T-cell infiltration, overcoming the stromal barrier in solid tumors.
Crossing the Blood-Brain Barrier
The blood-brain barrier (BBB) remains one of the most formidable obstacles in drug delivery, with nearly 98% of small molecule drugs unable to cross this highly selective interface. LNDDSs have increasingly attracted interest for brain targeting, crossing the BBB via both passive pathways and active mechanisms including receptor-mediated transcytosis and adsorptive-mediated transcytosis.
Surface functionalization with targeting ligands—transferrin, lactoferrin, insulin, or apolipoprotein E (ApoE) mimetic peptides—has been widely exploited. Ismail et al. engineered ApoE-peptide conjugated liposomal nanoparticles encapsulating temozolomide and artesunate that achieved deep tumor penetration and prolonged survival in a temozolomide-resistant glioblastoma (搜索) model via LDLR (搜索)-mediated transcytosis.
Cationic liposomes modified with transferrin-targeting peptides have also been designed as "smart bombs" to deliver CRISPR-Cas9 across the BBB for targeted P-glycoprotein (搜索) knockdown, enabling evaluation of drug pharmacoresistance in brain endothelial cell-containing BBB models.
Endo-Lysosomal Escape and Intracellular Targeting
Following cellular uptake, many internalized liposomes become trapped in endo-lysosomes, requiring efficient escape mechanisms. pH-responsive liposomes achieve endosomal escape through three proposed mechanisms: destabilization of the liposomal bilayer, fusion between liposomal and endosomal membranes, and disruption or rupture of the endosomal membrane.
Wu et al. demonstrated that calcium acetate-loaded pH-sensitive liposomes (PSL-Ca²⁺) enabled cytoplasmic delivery of a DNA-toxic agent through a two-step process: destabilization of the liposome backbone in acidic endo-lysosomal lumen releasing Ca²⁺, followed by calcium-induced endosomal swelling via the "proton sponge effect." In a breast cancer (搜索) mouse model, intratumoral drug concentrations 48 hours after treatment reached 56.3 µg/g—approximately 9-fold higher than non-pH-sensitive liposomes (6.76 µg/g; p = 0.001).
For mitochondrial targeting, surface conjugation with triphenylphosphonium (TPP⁺, MITO-Porter) or dequalinium (DQA, DQAsomes) has emerged as a versatile strategy, with growing relevance in oncology, neurodegeneration, and metabolic diseases.
External Stimuli: Thermal and Mechanical Destabilization
Thermosensitive LNDDSs engineered with phospholipids exhibiting gel-liquid crystalline phase transition temperatures of 40–42°C, such as dipalmitoyl phosphatidylcholine (DPPC), have shown promise. Regenold et al. reported that thermosensitive liposomal vinorelbine (ThermoVRL) combined with mild hyperthermia (39–43°C) induced complete tumor remission in three out of five mice, maintained until day 150 post-treatment. However, ThermoDox®, the most clinically advanced thermosensitive liposome, fell short in Phase III HEAT and OPTIMA trials for hepatocellular carcinoma (搜索), failing to extend progression-free survival.
Ultrasound-mediated mechanical destabilization operates through three effects: heating, acoustic streaming, and cavitation. Cavitation—the formation and oscillation of gas bubbles in response to pressure waves—can transiently create pores in cell membranes and open liposomal bilayers. The specific phospholipid composition significantly impacts ultrasound responsiveness: LNDDSs made with unsaturated DOPC show more ready ultrasound-triggered release than those with DSPC, while cholesterol incorporation reduces responsiveness.
Administration Routes and Translational Challenges
The review highlights that delivery efficiency of LNDDSs to target tissues remains below 2% following both intravenous and subcutaneous administration due to enzymatic degradation during systemic circulation. Following subcutaneous injection, less than 2% of LNDDSs ultimately reach lymph nodes, with the vast majority remaining sequestered at the injection site.
PEGylation, while providing "stealth" properties to extend circulation time, faces challenges from anti-PEG antibodies induced following repeated administration. Researchers are exploring cleavable or exchangeable PEG moieties; lipid nanoparticles modified with fast-shedding PEG-lipid (short acyl chain) enhance cellular uptake while reducing anti-PEG antibody generation compared to slow-shedding variants.
Emerging Opportunities
The review identifies several promising directions: hybrid and biomimetic liposomes merging synthetic lipid stability with natural vesicle sophistication; cationic liposomes and lipid nanoparticle-like formulations for RNA therapeutics and CRISPR-Cas genome editing; and artificial intelligence-guided formulation design enabling predictive optimization of lipid ratios, particle size, and surface chemistry.
"Future research efforts should focus on prolonging systemic circulation time, achieving controlled release at target tissues, improving the stability and extending the shelf life of LNDDSs to enhance transportability and storage, thereby facilitating clinical and industrial translation," the authors conclude.
The research was funded by the Cancer Society of New Zealand (搜索)'s National Research Grant (CSNZ2326). The authors declare no conflicts of interest.