Laddhad College of Pharmacy, Yelgaon, Buldhana, Tq. Buldhana, Dist. Buldhana (M.S.) – 443001
Conventional drug delivery systems (CDDSs) suffer from nonspecific drug distribution and uncontrolled release, leading to significant side effects. These limitations have driven the development of smart nanocarrier-based drug delivery systems (SDDSs), which enable targeted, controlled, and efficient drug delivery with reduced dosing frequency. SDDSs are particularly promising in cancer therapy, offering a site-specific alternative to conventional chemotherapy. This review summarizes recent advances in smart nanocarriers including liposomes, micelles, dendrimers, mesoporous silica nanoparticles, gold nanoparticles, magnetic nanoparticles, carbon nanotubes, and quantum dots highlighting their structure, synthesis, and functional ?smartness.? Additionally, toxicity, biocompatibility, key challenges, and future research directions of SDDSs are discussed, emphasizing their potential as powerful tools for single and multimodal drug delivery.
Drug delivery refers to the delivery of a pharmaceutical to a particular ailment site in order to achieve safer and efficient therapeutic outcomes. Drug release at the point of action is one of the main desired objectives of clinicians. However, safe transportation of drugs to the pathogenic sites and controlled release are the main challenges of Drug Delivery Systems (DDS). In this regard, researchers have been trying to develop innovative DDS that could enhance the efficacy of medications with no side effects. [1] The prelude of nanotechnology holds great promise for advances in biomedical research. Nanotechnology touches each edge of life beginning from nanoscale gadgets to drug delivery frameworks. Practicing nanotechnology for drugs transportation seems a smart approach for site-specific delivery of drug molecules because nanocarriers can shield a medication from degradation by dodging the reticuloendothelial framework. The high blood flow profile empowers transport via biological obstructions and expand the accessibility of medication at the focused intracellular compartments. [2] Nanodelivery systems have been found to improve administrative routes and biodistribution of drugs with low immunogenicity and side effects [3]. Nanocarriers deliver drugs to the ailment site either actively or passively. In the former case, peptides and antibodies coupled to the DDS are anchored with the receptor or the lipids or antigens at the targeted site by direct chemical conjugation. While passive delivery involves transportation of drug by the self-assembled nanostructured material and releasing the encapsulated drug at the target. Self-assembled nanostructures capable of encapsulating drugs in their hydrophobic environment are formed from a variety of building blocks such as polymers, proteins, nucleic acids, lipids, ceramics, or metals. [4]
Fig 1. Smart Nanocarriers For Targeted Drug Delivery. [5]
Types of Smart Nanocarriers- [7-15]
Polymeric nanoparticles are widely used as smart nanocarriers due to their tunable properties and biocompatibility. Various polymers, such as PLGA and chitosan, can be modified to achieve stimuliresponsive characteristics. These nanoparticles can encapsulate a range of therapeutic agents, from small molecules to proteins, allowing for versatile applications in drug delivery.
Liposomes, lipid-based vesicles that encapsulate drugs, can be designed to respond to specific stimuli. For instance, pH-sensitive liposomes can release their payload in acidic environments, making them ideal for cancer therapy. Additionally, light-sensitive liposomes can provide controlled release in targeted areas using external light sources.
Dendrimers are highly branched, nanoscale macromolecules that offer precise control over drug loading and release. Their architecture allows for multiple functionalization options, enabling the development of stimuli-responsive systems. Dendrimers can be designed to release their therapeutic payloads in response to specific enzymes or pH changes, making them suitable for targeted therapies.
Metal nanoparticles, such as gold and silver nanoparticles, have unique optical properties that can be exploited for controlled drug release. These nanoparticles can be conjugated with drugs and designed to release their payload upon exposure to specific wavelengths of light. This approach is particularly effective for photothermal therapy in cancer treatment.
Smart nanocarriers play a crucial role in gene therapy by delivering nucleic acids to target cells. For instance, enzyme-responsive nanoparticles can release siRNA in the presence of specific enzymes overexpressed in certain cancers, facilitating targeted gene silencing. This targeted delivery enhances the efficacy of gene therapies while minimizing off-target effects.
Smart nanocarriers are also being explored in vaccination strategies, where they can provide controlled release of antigens. This approach can enhance immune responses by ensuring that the antigen is released in a controlled manner, leading to improved vaccine efficacy.
Fig 2. Types of smart nanocarriers
Mechanisms of Targeted Delivery- [15-24]
1. Passive Targeting
Passive targeting strategies are predominantly based on the EPR effect, a phenomenon unique to solid tumors. This effect arises from the increased permeability of tumor vasculature compared with normal tissues. In tumors, the endothelial cell gaps range from 100 to 780 nm, depending on the cancer type, whereas in healthy tissues, these gaps are significantly smaller, approximately 5–10 nm. Consequently, nanocarriers within an optimal size range can preferentially extravasate into tumor sites. This mechanism has been successfully exploited in clinical applications, as demonstrated by the approved nanocarrier?based formulations Doxil© and Caelyx© . However, the passive targeting strategy has major limitations as the EPR effect is highly dependent on the tumor's intrinsic biological properties and varies significantly across tumor types, stages, and individuals. For example, metastatic liver cancer and pancreatic cancer exhibit low vascular permeability, resulting in reduced drug accumulation compared with highly vascularized tumors. As a result, nanocarriers relying solely on the EPR effect often face challenges in effectively targeting these tumors, thereby limiting the overall efficacy of therapeutic drugs.
2. Active Targeting
To enhance the cancer cell targeting capability, active targeting strategies have been developed by incorporating specific targeting moieties, such as antibodies, aptamers, and ligands, onto the surface of nanocarriers. These targeting molecules have high?affinity interaction with the proteins overexpressed by the tumor cells, including folate receptors, transferrin receptors (TfRs), and epithelial growth factor receptors. Upon reaching the tumor site, targeted nanocarriers interact with cancer cells through specific affinity interactions, facilitating their accumulation within the tumor tissue. Antibodies and antibody fragments, such as antigen?binding fragments (Fab) and single?chain variable fragments, play a crucial role in the development of actively targeting nanoparticle systems. These molecules can selectively bind to antigens overexpressed on cancer cells, thereby facilitating enhanced cellular uptake of therapeutic agents and nanoparticle drug delivery systems. Aptamers are single?stranded oligonucleotides where a library of random oligonucleotide sequences is exposed to the desired targeting ligand. They have emerged as promising active targeting molecules in nanocarrier systems due to their superior cancer?targeting capability. Aptamers can specifically recognize disease?associated biomarkers, such as receptors overexpressed on cancer cells, for instance, nucleolin, which is targeted by the AS1411 aptamer. One of the key advantages of aptamers is their high specificity and tunability, allowing precise recognition of target cells while minimizing off?target interactions. However, a major challenge is their limited in vivo stability, as unmodified aptamers are highly susceptible to nuclease degradation and rapid renal clearance. Ligand?based targeting strategy utilizes the fact that certain ligand molecules are specifically recognized by receptors that are overexpressed in cancer cells. Various ligand molecules such as hyaluronic acid (HA), FA, and CS have been shown to largely increase the targeting capabilities of nanocarriers. For example, FA?modified liposomal DOX and paclitaxel formulations have demonstrated preclinical success, shown enhanced tumor accumulation and reduced systemic toxicity. While these studies showed promising results for improved cancer treatment, they did not quantify the ligand density in the nanocarrier formulations. It is necessary to evaluate the optimal ligand concentration in the liposomes to ensure effective clinical translation.
3. Stimuli?Responsive Targeting
Stimuli?responsive nanocarriers represent a transformative approach in targeted drug delivery, engineered to release therapeutic payloads in response to an internal switch associated with disease microenvironments or external triggers. These active delivery systems utilize disease?related factors such as tumor?specific pH gradients, elevated glutathione (GSH) levels, overexpressed enzymes or hypoxia, as well as external stimuli like light, magnetic fields, or ultrasound. For example, pH?sensitive liposomes become destabilized in the acidic tumor microenvironment or within endosomal/lysosomal compartments, thereby enhancing intracellular drug delivery. Similarly, redox?responsive polymers break down in the high?GSH cytoplasm, improving the efficacy of encapsulated therapeutics. External triggers, such as near?infrared light or ultrasound, enable noninvasive control over drug release kinetics from the nanocarriers. Clinical trials have included thermosensitive liposomes (e.g., ThermoDox) in combination with hyperthermia for localized cancer therapy. Despite their promise, stimuli?responsive nanocarriers face some challenges. The heterogeneity of disease biomarkers, such as varying pH gradients across different tumors, can compromise the reliability of activation. External stimuli like light suffer from limited tissue penetration depth, restricting their utility to superficial or accessible lesions. Additionally, synthesis complexity increases the manufacturing costs of such nanocarriers and raises concerns about long?term stability.
Fig. 3. Mechanism of drug delivery
Applications of Nanocarrier?Based Targeted Delivery- [25-35]
Targeted delivery using nanocarriers has been widely investigated and applied in the treatment of various diseases, including genetic disorders, cardiovascular conditions, neurodegenerative diseases, and cancers.
1. Gene Disorders
A particularly promising application is in the treatment of monogenic disorders, where nanocarriers are employed to deliver genetic payloads that can modify or correct disease?causing genes. For example, lipid nanoparticles functionalized with liver?targeting ligands such as N?Acetylgalactosamine (GalNAc) have been used to specifically deliver CRISPR?based therapies targeting the ANGPTL3 gene to liver cells in both mouse and nonhuman primate models, offering a potential treatment for homozygous familial hypercholesterolemia. Similarly, multifunctional lipid nanoparticles modified with all?trans?retinamine have been shown to deliver plasmid DNA to the retina in the Rpe65 −/− mouse model for the treatment of Leber's congenital amaurosis caused by RPE65 gene mutations. In addition, a recent study reported the development of lipid nanoparticles functionalized with β?D?galactose?based ligands to enhance targeted delivery. These nanoparticles were specifically engineered to target the asialoglycoprotein receptor, which is abundantly expressed on the surface of hepatocytes. By facilitating receptor?mediated endocytosis, this strategy enabled the safe and efficient delivery of mRNA to the liver. The therapeutic mRNA encoded functional Factor VIII (FVIII), aiming to restore protein expression in hemophilia A, a genetic disorder caused by mutations or deficiencies in the F8 gene that results in the absence or dysfunction of FVIII protein. These targeted systems reduce off?target effects on other healthy tissues and improve therapeutic efficacy.
2. Neurodegenerative Diseases
Effective targeted delivery across the BBB is critical for treating neurodegenerative diseases. Nanocarriers can be functionalized with targeting molecules such as antibodies to deliver drugs to neurons and glial cells. For instance, polymer nanoparticles coated with polysorbate 80 and loaded with peptide inhibitors of polyglutamine aggregation have been used to treat Huntington's disease in both in vitro and in vivo models. In another study, polymeric nanoparticles modified with rabies virus glycoprotein peptide were reported to successfully cross the BBB and codeliver a therapeutic gene (shRNA) along with epigallocatechin?3?gallate to brain tissue in a mouse model of Alzheimer's disease (AD). This dual?delivery strategy effectively reduced amyloid?β plaque deposition and inhibited p?tau?related fibril formation. Lysosomal storage disorders (LSD), which primarily affect the central nervous system, often cause progressive and severe neurological impairments. To address this, a therapeutic strategy using TfR?targeted delivery of a plasmid encoding β?glucuronidase has been developed. Although the resulting enzyme activity was lower than physiological levels, it was still sufficient to provide therapeutic benefit. However, because this strategy depends on systemic intravenous administration, achieving sustained therapeutic benefits for chronic LSD conditions would require repeated dosing at intervals dictated by the duration of transgene expression. Recent advances include the development of stimuli?responsive nanocarriers that release their therapeutic cargo in response to elevated levels of ROS commonly found in the microenvironment of Parkinson's disease (PD) .
3. Cardiovascular Conditions
In cardiovascular therapy, nanocarriers are used to target atherosclerotic plaques, enhancing localized drug retention. For example, PLGA polymer nanoparticles conjugated with the mZD7349 peptide and loaded with simvastatin have been used to target dysfunctional endothelial cells, showing significantly higher therapeutic efficiency compared with nonconjugated nanoparticles. Lipid nanoparticles modified with a targeting peptide were used to specifically deliver anti?miR?712 to the endothelial surface of atherosclerotic lesions overexpressing vascular cell adhesion molecule 1 (VCAM1). In the partial carotid ligation model using ApoE−/− mice, this targeted delivery strategy effectively reduced atherosclerosis while minimizing off?target effects on other tissues. In addition to atherosclerosis treatment, targeted nanocarriers have shown promising potential in myocardial repair and regeneration after infarction. For example, a dual?targeted lipid?based complex functionalized with the antimyosin monoclonal antibody 2G4 (mAb 2G4) and the trans?activator of transcription (TAT) peptide has been developed to deliver therapeutic genes directly to ischemic myocardial tissue, improving localized therapeutic outcomes. Beyond lipid?based systems, polymeric nanoparticles have also been investigated for targeting acute myocardial infarction (MI). For instance, a peptide–polymer conjugate system was developed using a peptide sequence identified via phage display technology, which demonstrated high affinity for infarcted myocardial tissue. Delivery of this targeted system resulted in improved cardiac function, highlighting its therapeutic promise for post?MI tissue repair.
4. Cancer Therapy
Cancer therapy remains one of the most intensively investigated applications of targeted nanocarrier systems. By conjugating nanodrugs with ligands that selectively bind to receptors overexpressed on the surface of tumor cells, active targeting can be achieved with high specificity and efficiency. For instance, a HER2?targeted polymeric drug delivery system was developed using a star?shaped dendritic polymer conjugated with the topoisomerase I (TOP1) inhibitor SN?38 and the antigen?binding fragment of trastuzumab (HER2–Fab). This nanocarrier specifically recognizes and binds to cancer cells overexpressing HER2, resulting in significantly enhanced antitumor efficacy compared with nontargeted counterparts. In recent years, stimuli?responsive nanoparticles have emerged as a promising strategy for precise tumor targeting. Some functionalized nanoparticles are designed to respond to endogenous tumor microenvironment cues. Functionalized nanoparticles can also be externally activated by exogenous stimuli such as ultrasound, light illumination, or radiation. For example, a lipid–polymer hybrid nanoparticle platform has been developed to enable X?ray?induced photodynamic therapy (PDT) specifically targeting human colorectal cancer cells. This multifunctional nanocarrier coencapsulates verteporfin, a clinically approved photosensitizer, and 5?FU, a widely used chemotherapeutic agent, within a single delivery system. Upon exposure to X?ray irradiation at 4 Gy, the verteporfin generates ROS, leading to oxidative damage and apoptosis in tumor cells. In cancer vaccines, targeted nanocarriers can enhance the efficiency of immunotherapy by improving antigen delivery and stimulating stronger immune responses. For instance, poly (β?amino ester) ?based nanoparticles functionalized with T?cell targeting anti?CD3e f(ab′)2 fragments were used to specifically deliver CAR?encoding plasmid DNA to T cells in C57BL/6 mice. This targeted delivery system enhanced T?cell responses and triggered a robust antitumor effect. Iron oxide nanoparticles modified with mannose have been used to augment antitumor efficacy and enhance neoantigen vaccine through the repolarization of tumor?associated macrophages and improved coordination of immune cell activity.
Future Perspectives [36-40]
The future of nanocarrier-based drug delivery lies in its ability to move beyond uniform treatment strategies toward truly individualized therapeutic solutions. Advances in personalized nanomedicine are expected to enable the design of nanocarriers that respond to patient-specific biological cues, including genetic profiles, disease biomarkers, and tumor microenvironment characteristics. Such adaptability will allow therapies to be optimized for individual patients, improving therapeutic selectivity while minimizing systemic toxicity. Moreover, the development of multifunctional nanocarriers capable of simultaneous drug delivery, imaging, and real-time therapeutic monitoring is anticipated to further enhance treatment precision and enable dynamic clinical decision-making. In parallel, the application of artificial intelligence and computational modeling is poised to revolutionize nanocarrier design and development. AI-driven platforms can efficiently navigate the immense formulation landscape of nanocarriers, particularly lipid-based systems, by predicting optimal physicochemical properties and biological performance prior to experimental validation. Machine learning algorithms trained on experimental and clinical datasets can rapidly identify high-performing nanocarrier candidates, reduce reliance on trial-and-error approaches, and accelerate the transition from laboratory research to clinical application. As these technologies mature, they are expected to play a critical role in tailoring nanomedicines to specific disease subtypes and improving the success rate of clinical translation.
CONCLUSION
Targeted nanocarriers have emerged as a powerful strategy for enhancing drug delivery efficiency and advancing precision medicine. By enabling site-specific delivery and controlled release of therapeutic agents, these systems address many limitations associated with conventional therapies, including poor bioavailability, off-target effects, and drug resistance. Although notable progress has been achieved in preclinical development, challenges related to scalable manufacturing, regulatory standardization, and long-term safety remain key barriers to widespread clinical adoption. Overall, continued interdisciplinary collaboration among materials scientists, pharmaceutical researchers, clinicians, and data scientists is essential for translating nanocarrier technologies into effective clinical solutions. With sustained research efforts and technological innovation, targeted nanocarriers are expected to significantly improve therapeutic outcomes and contribute to the next generation of personalized and effective medical treatments.
REFERENCES
Komal Lahase, Shital Kharat, Namrata Deshmukh, Payal Suradkar, Gayatri Rajguru, Gauri Talpate, Avanti Girdekar*, Smart Nanocarriers For Targeted Drug Delivery: Recent Advances and clinical Perspectives, Int. J. Med. Pharm. Sci., 2025, 1 (12), 71-79. https://doi.org/10.5281/zenodo.17994483
10.5281/zenodo.17994483
