Drug Delivery Systems for Natural Medicines in Cancer Therapy.

Cancer stands as a prominent global cause of mortality, with chemotherapy using synthetic drugs being the predominant treatment method. Despite its high success rate, this approach is constrained by substantial side effects. Herbal medicines, known for their diverse bioactive components, exhibit promising anticancer attributes. The drug delivery systems can improve the precision of delivering these herbal compounds, enhancing efficacy while minimizing potential side effects. Various platforms, such as nanoparticle-based carriers, liposomes, and polymeric micelles, are investigated for encapsulating and delivering herbal components to cancer cells. These systems not only enhance the bioavailability of herbal compounds but also facilitate controlled release, sustained drug circulation, and improved cellular uptake. This comprehensive review focuses on the recent advancement in the field of drug delivery systems employed in the delivery of plant-derived anticancer compounds. It categorizes carriers into organic and inorganic nanoparticles, addressing their application in enhancing the safety and efficacy of plant-derived anticancer compounds alongside associated challenges. The review concludes by outlining recent investigations into drug delivery systems aimed at increasing the efficacy of plant-derived anticancer compounds. Future research in this field should emphasize experiments in animal models and potential clinical translation.

Scope and Application of Hot Melt Extrusion in the Development of Controlled and Sustained Release Drug Delivery Systems.

Controlled-release drug delivery systems (CRDDS) are more beneficial than conventional immediate release (IRDDS) for reduced intake, prolonged duration of action, lesser adverse effects, higher bioavailability, etc. The preparation of CRDDS is more complex than IRDDS. The hot melt extrusion (HME) technique is used for developing amorphous solid dispersion of poorly water soluble drugs to improve their dissolution rate and oral bioavailability. HME can be employed to develop CRDDS. Sustained release delivery systems (SRDDS), usually given orally, can also be developed using HME. This technique has the advantages of using no organic solvent, converting crystalline drugs to amorphous, improving bioavailability, etc. However, the heat sensitivity of drugs, miscibility between drug-polymer, and the availability of a few polymers are some of the challenges HME faces in developing CRDDS and SRDDS. The selection of a suitable polymer and the optimization of the process with the help of the QbD principle are two important aspects of the successful application of HME. In this review, strategies to prepare SRDDS and CRDDS using HME are discussed with its applications in research.

Recent advances in modified chitosan-based drug delivery systems for transmucosal applications: A comprehensive review.

Recently, transmucosal drug delivery systems (TDDSs) have been extensively studied because they protect therapeutic agents from degradation; improve drug residence time at the mucosal membranes; and facilitate sustained drug release for a prolonged period. Chitosan is a well-researched polymeric excipient due to its biocompatibility, non-toxicity, biodegradability, mucoadhesive, antimicrobial, and low immunogenicity. Its limited mucoadhesiveness in the physiological environment necessitated its chemical modification. This review highlights the recent advances in the chemical modification of chitosan with various chemical groups to generate various functionalized chitosan derivatives, such as thiolated, acrylated, methacrylated, boronated, catechol, and maleimide-functionalized chitosans with superior mucoadhesive capabilities compared to the parent chitosan. Moreover, it presents the different prepared dosage forms, such as tablets, hydrogels, films, micro/nanoparticles, and liposomes/niosomes for drug administration within various mucosal routes including oral, buccal, nasal, ocular, colonic, intravesical, and vaginal routes. The reported data from preclinical studies of these pharmaceutical formulations have revealed the controlled and target-specific delivery of therapeutics because of their formation of covalent bonds with thiol groups on the mucosal surface. All functionalized chitosan derivatives exhibited long drug residence time on mucosal surfaces and sustainable drug release with excellent cellular permeability, drug efficacy, and biocompatibility. These promising data could be translated from the research laboratories to the clinics with consistent and intensive research effort.

Intrathecal drug delivery systems for cancer pain: A retrospective analysis at a single tertiary medical center in China.

Objective: Intrathecal drug delivery systems (IDDS) have been clinically applied to treat refractory cancer-related pain for years. In this study, we demonstrate the current clinical practice and outcomes of IDDS for cancer pain management over a 3-year period at a single tertiary medical center in China. Methods: Patients who received IDDS implantation for cancer-related pain from 2021 to 2023 were identified. The electronic medical records of all eligible patients were retrospectively reviewed for study data including baseline characteristics, IDDS variables and postoperative clinical outcomes. Results: A total of 96 consecutive individuals were identified for analysis and complete follow-up information was available in 72 patients with a follow-up rate of 75 %. Patients were 49.0 % female with a mean age of 62 ± 10 years. The top five cancer types in IDDS population were lung (34.4 %), colorectal (17.7 %), pancreatic (11.5 %), breast (5.2 %) and liver (4.2 %) cancer. The median duration from cancer diagnosis to IDDS implantation was 24 months (interquartile range [IQR] 12-48 months) and from pain onset to IDDS implantation was 6 months (IQR 2-12 months). In addition, the median oral morphine equivalents (OME) daily dose was 290 mg (IQR 100-632 mg). Mean NRS was 7.5 ± 0.8 before implantation and decreased to an average of 3.0 ± 1.1 after IDDS (p < 0.001). Median overall survival after IDDS implantation was 3 months (IQR 2-6 months). Overall, 75 % family members of cancer patients were satisfied with IDDS in relieving cancer pain. Conclusion: IDDS therapy is a valuable option for patients suffering from cancer pain. More and more cancer pain patients receive IDDS to treat pain during the 3-year study period.

3D printed microneedles: revamping transdermal drug delivery systems.

One of the advancements of the transdermal drug delivery system (TDDS) is the development of microneedles (MNs). These micron-sized needles are used for delivering various types of drugs to address the disadvantage of other transdermal techniques as well as oral drug delivery systems. MNs have high patient acceptance due to self-administration with minimally invasive and pain compared to the parenteral drug delivery. Over the years, various methods have been adopted to evolve the MNs and make them more cost-effective, accurate, and suitable for multiple applications. One such method is the 3D printing of MNs. The development of MN platforms using 3D printing has been made possible by improved features like precision, printing resolution, and the feasibility of using low-cost raw materials. In this review, we have tried to explain various types of MNs, fabrication methods, materials used in the formulation of MNs, and the recent applications that utilize 3D-printed MNs.

Analysis of Structural Changes of pH-Thermo-Responsive Nanoparticles in Polymeric Hydrogels.

The pH- and thermo-responsive behavior of polymeric hydrogels MC-co-MA have been studied in detail using dynamic light scattering DLS, scanning electron microscopy SEM, nuclear magnetic resonance (1H NMR) and rheology to evaluate the conformational changes, swelling-shrinkage, stability, the ability to flow and the diffusion process of nanoparticles at several temperatures. Furthermore, polymeric systems functionalized with acrylic acid MC and acrylamide MA were subjected to a titration process with a calcium chloride CaCl2 solution to analyze its effect on the average particle diameter Dz, polymer structure and the intra- and intermolecular interactions in order to provide a responsive polymer network that can be used as a possible nanocarrier for drug delivery with several benefits. The results confirmed that the structural changes in the sensitive hydrogels are highly dependent on the corresponding critical solution temperature CST of the carboxylic (-COOH) and amide (-CONH2) functional groups and the influence of calcium ions Ca2+ on the formation or breaking of hydrogen bonds, as well as the decrease in electrostatic repulsions generated between the polymer chains contributing to a particle agglomeration phenomenon. The temperature leads to a re-arrangement of the polymer chains, affecting the viscoelastic properties of the hydrogels. In addition, the diffusion coefficients D of nanoparticles were evaluated, showing a closeness among with the morphology, shape, size and temperature, resulting in slower diffusions for larger particles size and, conversely, the diffusion in the medium increasing as the polymer size is reduced. Therefore, the hydrogels exhibited a remarkable response to pH and temperature variations in the environment. During this research, the functionality and behavior of the polymeric nanoparticles were observed under different analysis conditions, which revealed notable structural changes and further demonstrated the nanoparticles promising high potential for drug delivery applications. Hence, these results have sparked significant interest in various scientific, industrial and technological fields.

Drug Delivery Strategies for Age-Related Diseases.

Drug delivery systems (DDSs) enable the controlled release of drugs in the body. DDSs have attracted increasing attention for the treatment of various disorders, including cancer, inflammatory diseases, and age-related diseases. With recent advancements in our understanding of the molecular mechanisms of aging, new target molecules and drug delivery carriers for age-related diseases have been reported. In this review, we will summarize the recent research on DDSs for age-related diseases and identify DDS strategies in the treatment of age-related diseases.

Nano-Based Drug Approaches to Proliferative Vitreoretinopathy Instead of Standard Vitreoretinal Surgery.

Proliferative vitreoretinopathy (PVR) has traditionally been managed with vitreoretinal surgery. Although there have been several recent innovations in this surgery to make the retinal approach as uninvasive as possible, the outcomes remain unsatisfactory. Significant complications remain and the complexity of the surgical approach is challenging. The focus of this review was to investigate and discuss the effectiveness of nanomedicine, featuring a wide range of drugs and molecules, as a novel potential treatment for PVR. To date, ocular drug delivery remains a significant issue due to the physiological and anatomical barriers, dynamic or static, which prevent the entry of exogenous molecules. We tried to summarize the nanotechnology-based ophthalmic drugs and new nanoparticles currently under research, with the intention of tackling the onset and development of PVR. The purpose of this review was to thoroughly and analytically examine and assess the potential of nano-based techniques as innovative strategies to treat proliferative vitreoretinopathy (PVR). This study aimed to emphasize the breakthroughs in nanomedicine that provide promising therapeutic options to enhance the results of vitreoretinal surgery and halt disease progression, considering the complexity and difficulty of PVR treatment. The future directions of the nanoparticles and nanotherapies applied to PVR highlight the importance of investing in the development of better designs and novel ophthalmic formulations in order to accomplish a mini-invasive ocular approach, replacing the standard-of-care vitreoretinal surgery.

Transforming Healthcare with Nanomedicine: A SWOT Analysis of Drug Delivery Innovation.

Objective: Nanomedicine represents a transformative approach in biomedical applications. This study aims to delineate the application of nanomedicine in the biomedical field through the strengths, weaknesses, opportunities, and threats (SWOT) analysis to evaluate its efficacy and potential in clinical applications. Methods: The SWOT analysis framework was employed to systematically review and assess the internal strengths and weaknesses, along with external opportunities and threats of nanomedicine. This method provides a balanced consideration of the potential benefits and challenges. Results: Findings from the SWOT analysis indicate that nanomedicine presents significant potential in drug delivery, diagnostic imaging, and tissue engineering. Nonetheless, it faces substantial hurdles such as safety issues, environmental concerns, and high development costs. Critical areas for development were identified, particularly concerning its therapeutic potential and the uncertainties surrounding long-term effects. Conclusion: Nanomedicine holds substantial promise in driving medical innovation. However, successful clinical translation requires addressing safety, cost, and regulatory challenges. Interdisciplinary collaboration and comprehensive strategic planning are crucial for the safe and effective application of nanomedicine.

Development of modular polymeric nanoparticles for drug delivery using amine reactive chemistry.

Curcumin has been explored for its anti-cancer potential, but is severely limited by its hydrophobicity and sensitivity to light and water. In this study, poly (lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) were synthesized to encapsulate curcumin via single emulsion method to improve curcumin stability and bioavailability. The PLGA NPs were coated with oligomeric chitosan (COS) and RGD peptide (a peptide consisting of Arg-Gly-Asp) using amine-reactive chemistry (NHS and EDC). Both COS and RGD had been previously shown to accumulate and target many different types of cancer cells. NPs were characterised based on size distribution, zeta potential, and binding efficiency of RGD peptide. They were also evaluated on encapsulation efficiency, and stability, of curcumin within the NPs. OVCAR-3 cancer cells were treated with COS and RGD-coated PLGA NPs loaded with Coumarin-6 dye for fluorescent imaging of cell uptake. They were also treated with curcumin-loaded NPs to determine cytotoxicity and effectiveness of delivery. The NPs exhibited size distribution and zeta potential within expected values, though binding efficiency of RGD was low. Curcumin-loaded NPs showed significant increase in cytotoxicity over free (unencapsulated) curcumin, and void (empty) NPs, suggesting successful delivery of curcumin as an anti-cancer agent; the performance of COS and RGD coated NPs over bare PLGA NPs was inconclusive, however, optimization will be required to improve formulation during the coating steps. This method of NP synthesis serves as proof of concept for a modular solution to the development of various coated polymeric NPs for other drugs or applications.

Phytovesicular Nanoconstructs For Advanced Delivery of Medicinal Metabolites: An In-Depth Review.

Phytochemicals, the bioactive compounds in plants, possess therapeutic benefits, such as antimicrobial, antioxidant, and pharmacological activities. However, their clinical use is often hindered by poor bioavailability and stability. Phytosome technology enhances the absorption and efficacy of these compounds by integrating vesicular systems like liposomes, niosomes, transfersomes, and ethosomes. Phytosomes offer diverse biological benefits, including cardiovascular protection through improved endothelial function and oxidative stress reduction. They enhance cognitive function and protect against neurodegenerative diseases in the nervous system, aid digestion and reduce inflammation in the gastrointestinal system, and provide hepatoprotective effects by enhancing liver detoxification and protection against toxins. In the genitourinary system, phytosomes improve renal function and exhibit anti-inflammatory properties. They also modulate the immune system by enhancing immune responses and reducing inflammation and oxidative stress. Additionally, phytosomes promote skin health by protecting against UV radiation and improving hydration and elasticity. Recent patented phytosome technologies have led to innovative formulations that improve the stability, bioavailability, and therapeutic efficacy of phytochemicals, although commercialization challenges like manufacturing scalability and regulatory hurdles remain. Secondary metabolites from natural products are classified into primary and secondary metabolites, with a significant focus on terpenoids, phenolic compounds, and nitrogen-containing compounds. These metabolites have notable biological activities: antimicrobial, antioxidant, antibiotic, antiviral, anti-inflammatory, and anticancer effects. In summary, this review amalgamates the latest advancements in phytosome technology and secondary metabolite research, presenting a holistic view of their potential to advance therapeutic interventions and contribute to the ever-evolving landscape of natural product-based medicine.

Fabrication of 3D printed mutable drug delivery devices: a comparative study of volumetric and digital light processing printing.

Mutable devices and dosage forms have the capacity to dynamically transform dimensionally, morphologically and mechanically upon exposure to non-mechanical external triggers. By leveraging these controllable transformations, these systems can be used as minimally invasive alternatives to implants and residence devices, foregoing the need for complex surgeries or endoscopies. 4D printing, the fabrication of 3D-printed structures that evolve their shape, properties, or functionality in response to stimuli over time, allows the production of such devices. This study explores the potential of volumetric printing, a novel vat photopolymerisation technology capable of ultra-rapid printing speeds, by comparing its performance against established digital light processing (DLP) printing in fabricating hydrogel-based drug-eluting devices. Six hydrogel formulations consisting of 2-(acryloyloxy)ethyl]trimethylammonium chloride solution, lithium phenyl-2,4,6-trimethylbenzoylphosphinate, varying molecular weights of the crosslinking monomer, poly(ethylene glycol) diacrylate, and paracetamol as a model drug were prepared for both vat photopolymerisation technologies. Comprehensive studies were conducted to investigate the swelling and water sorption profiles, drug release kinetics, and physicochemical properties of each formulation. Expandable drug-eluting 4D devices were successfully fabricated within 7.5 s using volumetric printing and were shown to display equivalent drug release kinetics to prints created using DLP printing, demonstrating drug release, swelling, and water sorption properties equivalent to or better than those of DLP-printed devices. The reported findings shed light on the advantages and limitations of each technology for creating these dynamic drug delivery systems and provides a direct comparison between the two technologies, while highlighting the promising potential of volumetric printing and further expanding the growing repertoire of pharmaceutical printing.

Emerging Trends in the Application of Extracellular Vesicles as Novel Oral Delivery Vehicles for Therapeutics in Inflammatory Diseases.

Inflammation involves complex immune responses where cytokines such as TNF-α, IL-1, and IL-6 promote vasodilation and increased vascular permeability to facilitate immune cell migration to inflammation sites. Persistent inflammation is linked to diseases like cancer, arthritis, and neurodegenerative disorders. Although oral anti-inflammatory drugs are favored for their non-invasiveness and cost-effectiveness, their efficacy is often compromised due to gastrointestinal degradation and limited bioavailability. Recent advancements highlight the potential of extracellular vesicles (EVs) as nanocarriers that enhance drug delivery by encapsulating therapeutic agents, ensuring targeted release and reduced toxicity. These EVs, derived from dietary sources and cell cultures, exhibit excellent biocompatibility and stability, presenting a novel approach in anti-inflammatory therapies. This review discusses the classification and advantages of orally administered EVs (O-EVs), their mechanism of action, and their emerging role in treating inflammatory conditions, positioning them as promising vectors in the development of innovative anti-inflammatory drug delivery systems.

New Horizons in Antiretroviral Drug Delivery Systems for HIV Management

INTRODUCTION: Human Immunodeficiency Virus (HIV) infection is still a major global problem, whose drug treatment consists of prophylactic prevention and antiretroviral combination therapy for better pharmacological efficacy and control of the circulating virus. However, there are still pharmacological problems that need to be overcome, such as low aqueous solubility of drugs, toxicity, and low patient adherence. Drug delivery technologies can be used to overcome these barriers. OBJECTIVE: This review summarized the latest drug delivery systems for HIV treatment. Initially, an overview of the current therapy was presented, along with the problems it presents. Then, the latest drug delivery systems used to overcome the challenges imposed in conventional HIV therapy were discussed. CONCLUSION: This review examines innovative approaches for HIV treatment, where various drug delivery systems have shown significant advantages, such as high drug encapsulation, improved solubility, and enhanced bioavailability both in vitro and in vivo. Strategies like cyclodextrins, solid dispersions, microneedles, and nanoparticles are explored to address challenges in drug solubility, bioavailability, and administration routes. Despite progress, obstacles like limited clinical trials and industrial scalability hinder the widespread adoption of these formulations, emphasizing the need for further research and collaboration to optimize and ensure accessibility of innovative HIV therapies, mainly in regions where access to HIV treatment is scarce and remains a challenge.

Lipidic drug delivery systems are responsive to the human microbiome.

In vitro and in vivo tests for therapeutic agents are typically conducted in sterile environments, but many target areas for drug delivery are home to thousands of microbial species. Here, we examine the behaviour of lipidic nanomaterials after exposure to representative strains of four bacterial species found in the gastrointestinal tract and skin. Small angle X-ray scattering measurements show that the nanostructure of monoolein cubic and inverse hexagonal phases are transformed, respectively, into inverse hexagonal and inverse micellar cubic phases upon exposure to a strain of live Staphylococcus aureus often present on skin and mucosa. Further investigation demonstrates that enzymatic hydrolysis and cell membrane lipid transfer are both likely responsible for this effect. The structural responses to S. aureus are rapid and significantly reduce the rate of drug release from monoolein-based nanomaterials. These findings are the first to demonstrate how a key species in the live human microbiome can trigger changes in the structure and drug release properties of lipidic nanomaterials. The effect appears to be strain specific, varies from patient to patient and body region to body region, and is anticipated to affect the bioapplication of monoglyceride-based formulations.

Nanoparticle-Based Therapies for Neurotropic Viral Infections: Mechanisms, Challenges, and Future Prospects.

Neurotropic viral infections pose a significant challenge due to their ability to target the central nervous system and cause severe neurological complications. Traditional antiviral therapies face limitations in effectively treating these infections, primarily due to the blood-brain barrier, which restricts the delivery of therapeutic agents to the central nervous system. Nanoparticle-based therapies have emerged as a promising approach to overcome these challenges. Nanoparticles offer unique properties that facilitate drug delivery across biological barriers, such as the blood-brain barrier, and can be engineered to possess antiviral activities.

Cellular probing using phytoceuticals encapsulated advanced delivery systems in ameliorating lung diseases: Current trends and future prospects.

Chronic respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma have posed a significant healthcare and economic cost over a prolonged duration worldwide. At present, available treatments are limited to a range of preventive medicines, such as mono- or multiple-drug therapy, which necessitates daily use and are not considered as viable treatments to reverse the inflammatory processes of airway remodelling which is inclusive of the alteration of intra and extracellular matrix of the airway tract, death of epithelial cells, the increase in smooth muscle cell and the activation of fibroblasts. Hence, with the problem in mind a considerable body of study has been dedicated to comprehending the underlying factors that contribute to inflammation within the framework of these disorders. Hence, adequate literature that has unveiled the necessary cellular probing to reduce inflammation in the respiratory tract by improving the selectivity and precision of a novel treatment. However, through cellular probing cellular mechanisms such as the downregulation of various markers, interleukin 8, (IL-8), Interleukin 6 (IL-6), interleukin 1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) have been uncovered. Hence, to target such cellular probes implementation of phytoceuticals encapsulated in an advanced drug delivery system has shown potential to be a solution with in vitro and in vivo studies highlighting their anti-inflammatory and antioxidant effects. However, the high costs associated with advanced drug delivery systems and the limited literature focused exclusively on nanoparticles pose significant challenges. Additionally, the biochemical characteristics of phytoceuticals due to poor solubility, limited bioavailability, and difficulties in mass production makes it difficult to implement this product as a treatment for COPD and asthma. This study aims to examine the integration of many critical features in the context of their application for the treatment of chronic inflammation in respiratory disorders.

Recent Advances in Nano-Based Drug Delivery Systems for Treatment of Liver Cancer.

Liver cancer is one of the aggressive primary tumors as evident by high rate of incidence and mortality. Conventional treatments (e.g. chemotherapy) suffer from various drawbacks including wide drug distribution, low localized drug concentration, and severe off-site toxicity. Therefore, they cannot satisfy the mounting need for safe and efficient cancer therapeutics, and alternative novel strategies are needed. Nano-based drug delivery systems (NDDSs) are among these novel approaches that can improve the overall therapeutic outcomes. NDDSs are designed to encapsulate drug molecules and target them specifically to liver cancer. Thus, NDDSs can selectively deliver therapeutic agents to the tumor cells and avoid distribution to off-target sites which should improve the safety profile of the active agents. Nonetheless, NDDSs should be well designed, in terms of the preparing materials, nanocarriers structure, and the targeting strategy, in order to accomplish these objectives. This review discusses the latest advances of NDDSs for cancer therapy with emphasis on the aforementioned essential design components. The review also entails the challenges associated with the clinical translation of NDDSs, and the future perspectives towards next-generation NDDSs.

Oral formulations for highly lipophilic drugs: Impact of surface decoration on the efficacy of self-emulsifying drug delivery systems.

AIM: To evaluate the impact of the surface decoration of cannabidiol (CBD) loaded self-emulsifying drug delivery systems (SEDDS) on the efficacy of the formulations to cross the various barriers faced by orally administered drugs. METHODS: Polyethylene glycol (PEG)-free polyglycerol (PG)-based SEDDS, mixed zwitterionic phosphatidyl choline (PC)/PEG-containing SEDDS and PEG-based SEDDS were compared regarding stability against lipid degrading enzymes, surface properties, permeation across porcine mucus, cellular uptake and cytocompatibility. RESULTS: SEDDS with a size of about 200 nm with narrow size distributions were developed and loaded with 20-21 % of CBD. For PG containing PEG-free SEDDS increased degradation by lipid degrading enzymes was observed compared to PEG-containing formulations. The surface hydrophobicity of placebo SEDDS increased in the order of PG-based to mixed PC/PEG-based to PEG-based SEDDS. The influence of this surface hydrophobicity was also observed on the ability of the SEDDS to cross the mucus gel layer where highest mucus permeation was achieved for most hydrophobic PEG-based SEDDS. Highest cellular internalization was observed for PEG-based Lumogen Yellow (LY) loaded SEDDS with 92 % in Caco-2 cells compared to only 30 % for mixed PC/PEG-based SEDDS and 1 % for PG-based SEDDS, leading to a 100-fold improvement in cellular uptake for SEDDS having highest surface hydrophobicity. For cytocompatibility all developed placebo SEDDS showed similar results with a cell survival of above 75 % for concentrations below 0.05 % on Caco-2 cells. CONCLUSION: Higher surface hydrophobicity of SEDDS to orally deliver lipophilic drugs as CBD seems to be a promising approach to increase the intracellular drug concentration by an enhanced permeation through the mucus layer and cellular internalization.

Topical calcineurin and mammalian target of rapamycin inhibitors in inflammatory dermatoses: Current challenges and nanotechnology­based prospects (Review).

Topical therapy remains a critical component in the management of immune­mediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroid­free therapeutic alternatives. Despite their potential for skin­selective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrier­based delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential anti­inflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hard­to­formulate' macromolecules in the context of psoriasis and atopic dermatitis.