A major limitation of conventional two and three-dimensional preclinical in vitro cancer models is their inability to reproduce the drug-delivery barriers. Tumor assembloids, which integrate patient-derived cancer cells with stromal, endothelial, and immune components in three-dimensional architectures, provide a manipulable framework for simulating these multicellular impediments. This review specifically examines the application of tumor assembloids to investigate drug delivery constraints, including stromal exclusion, vascular transport, immune-mediated resistance, penetration gradients, and spatially heterogeneous drug exposure. We compared three major construction strategies, including self-assembly, 3D bioprinting, and microfluidic compartmentalization, and evaluated their respective strengths for drug assessment. We also discussed assembloids' current limitations, including reproducibility, incomplete physiological dynamics, insufficient spatial analytics, and the need for standardized benchmarking. Overall, tumor assembloids represent promising mechanistic platforms for studying tumor drug delivery barriers. However, broader clinical application will necessitate rigorous validation and harmonized assay standards.
Tumor drug resistance is a major clinical challenge that limits the efficacy of chemotherapy, targeted therapy, and immunotherapy, thereby contributing to tumor recurrence, metastasis, and reduced overall patient survival rates. Recent studies reveal that extracellular vesicles (EVs) in the tumor microenvironment act as key mediators of intercellular communication. They play a central role in mediating tumor cell resistance by transporting functional cargo, including RNA, proteins, and lipids. This review outlines the mechanisms of EV-mediated tumor resistance, including key processes such as drug efflux, evasion of apoptosis, maintenance of epithelial-mesenchymal transition and cancer stem cell phenotypes, remodeling of the immune microenvironment, metabolic reprogramming, and expansion of resistant cell populations. It also discusses the use of EVs as biomarkers of resistance and their associated detection technologies. Furthermore, this paper highlights therapeutic strategies for reversing drug resistance through engineered EVs, including the delivery of small molecules, nucleic acid therapeutics, and key bioactive components. It also reviews current preclinical studies and progress toward clinical translation of EV-based resistance reversal strategies. This review aims to elucidate the role and translational potential of EVs in tumor drug resistance through a systematic approach that integrates mechanism exploration, biomarker identification, engineered drug delivery, and clinical translation. It provides a comprehensive reference to facilitate further advances in this field, from basic research to clinical practice.
Self-microemulsifying drug delivery systems (SMEDDS) containing volatile phytotherapeutics such as thymol (T), carvacrol (C), and eugenol (E) present significant formulation challenges, even when solidified. Their instability and interactions with coatings often hinder intestinal delivery. To address these limitations, we developed solid SMEDDS consisting of pellets (microcrystalline cellulose/magnesium aluminometasilicate/chitosan) and enteric capsules (CEC) for enhanced intestinal delivery. Based on solubility and pseudo-ternary phase diagrams, SMEDDS formulations (SES1-3) differing in component ratios (glycerol monooleate/caprylocaproyl macrogol-8 glycerides/diethylene glycol monoethyl ether) with 5% w/w of each drug were identified, demonstrating nano-scale droplet sizes (PDI <0.4) and showing no phase separation over 6 months. Thermodynamic stability and liquid-state NMR revealed particle size variations with preserved structural integrity. The lead formulation SES1 exhibited superior ex-vivo intestinal permeation (T-SES1). CECs filled with T-, C-, and E-loaded SES1 pellets, respectively, prepared via extrusion/spheronization, exhibited in-vitro gastro-resistant release, and achieved > 85% drug release within 120  min after a pH change to 6.8 during a one-year stability study (25 °C; 60% RH). FTIR-ATR analysis of the CEC internal surface confirmed the temperature-dependent restructuring of hypromellose and E sorption, a phenomenon not observed with C or T, which is likely attributable to physicochemical distinctions. Oral administration of CEC with T-SES1-pellets (0.5  mg/kg) in piglets demonstrated a delayed peak plasma concentration (Cmax 11.67  ng/mL at 9 h) and sustained systemic exposure (AUC 119.8 ng·h/mL). These in-vivo findings substantiate the gastro-protective effect and enhanced intestinal absorption, positioning the pellet/CEC system as a promising strategy for the application of volatile phytotherapeutics in current pharmacotherapy.
Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, and current systemic therapies are limited by advanced-stage diagnosis, dose-limiting toxicity, drug resistance, and incomplete response rates. Oral nano-drug delivery systems (nano-DDS) are being explored as patient-friendly platforms to improve gastrointestinal protection, intestinal absorption, and hepatic exposure of anticancer agents. However, the evidence base remains uneven: only a minority of HCC nano-DDS studies have been validated through oral administration, whereas many mechanistically important studies rely on intravenous, other parenteral, or in vitro models. To avoid overstatement, this review maps the literature according to route of administration, model relevance, comparator choice, pharmacokinetic reporting, and translational readiness. We synthesize design strategies for polymeric, lipid-based, inorganic, biomimetic, stimulus-responsive, ligand-targeted, magnetic, natural product-loaded, and microbiome-modulating systems, while distinguishing direct oral evidence from non-oral mechanistic evidence. We further emphasize practical requirements for clinical translation, including clinically meaningful comparators such as marketed oral formulations, fed/fasted and portal pharmacokinetics, orthotopic and fibrotic/cirrhotic HCC models, long-term hepatotoxicity and immunotoxicity testing, gut microbiome safety assessment, manufacturing reproducibility, and minimum characterization packages under biorelevant gastrointestinal conditions. Rather than presenting oral nano-DDS as a mature therapeutic class, this review frames the field as a promising but incompletely validated area that requires route-specific validation and standardized go/no-go criteria before clinical development for HCC.
Poor aqueous solubility remains a major barrier to small-molecule drug development. Pharmaceutical nanosuspensions, composed mainly of drug nanocrystals stabilized by small amounts of excipients, can improve dissolution and have been translated into several oral products and long-acting injectables. However, their simple compositions do not make them biologically inert. Nanosizing changes the surface area, dissolution, interfacial properties, aggregation, and interactions with biological fluids, thereby affecting local and systemic safety. This review examines nanosuspension safety from a product-level perspective. It focuses on formulation states generated during storage, handling, administration, and biological exposure, with attention to particle-size distribution, large-particle tails, stabilizer coverage and free excipient, crystal form, dissolution behavior, redispersibility, and in-use stability. These attributes are linked to blood compatibility, complement activation, immune responses, route-specific toxicity, biodistribution, macrophage-associated retention, depot persistence, clinical experience, and regulatory translation. Current evidence supports nanosuspensions under well-controlled conditions, especially for oral nanocrystal products and selected long-acting injectables. Key uncertainties remain for repeated intravenous use, chronic pulmonary exposure, particle-specific biodistribution, depot reversibility, long-term tissue exposure, and vulnerable populations. Safety assessment should, therefore, connect critical quality attributes with route-relevant exposure and biological responses, providing a basis for safety by design.
Breast cancer, one of the leading cancer types, directly contributes to cancer-related mortality, but new therapies are required to improve treatment efficiency. Nanoparticle-based strategies have already introduced the most radical advances in this regard, from their first formulation through their development to the next generation as promising candidates. The present review provides an overview of nanoparticle-based strategies in breast cancer, their development, and their state of the art. The review addresses the diverse formulation of nanoparticles, including liposomes, dendrimers, and metallic nanoparticles, as well as their respective roles in drug delivery: bioavailability, focused therapeutic intervention, and lower systemic toxicity. This review covers studies on the engineering of nanoparticles for improved drug delivery, including cancer-targeted delivery to tumors and optimization within the tumor microenvironment. Additionally, new nanosized drugs may also be utilized for novel modification of nanoparticle composition for combination therapeutics, which allows pharmacological agents to enter the tumor microenvironment by combined treatment with diverse types of other agents, to provide a synergistic, effective treatment in real time, in addition to real-time monitoring. Stimuli-responsive nanoparticles, which release the drug according to the appropriate stimulus signal to provide greater accuracy and regulation in delivering the drug, are also under investigation. This review notes trends in personalized nanomedicine and nanoparticle-mediated immunotherapy that target personalized patient and immune responses, among others. Other exciting areas for nanoparticle research include AI-based optimal design and sustainable biodegradable materials aimed at maintaining nanoparticle safety. Nanoparticle-based therapies are a unique new frontier in breast cancer therapy. They have considerable clinical potential, offer promise for patient-specific treatment, and warrant further investigation in breast cancer, particularly in advanced targeting mechanisms, multifunctional approaches, and individualized interventions.
Introduction: Pain is one of the most common reasons why patients seek medical care, and chronic pain is now recognized as a major health problem worldwide. Better understanding of pain mechanisms has shown the importance of distinguishing nociceptive, neuropathic, and nociplastic pain in order to choose the most effective treatment. In recent years, topical analgesics have gained increasing attention because they can provide pain relief directly at the site of application while reducing systemic exposure and the risk of adverse effects. This is especially important in older adults, patients with multiple diseases, and those exposed to polypharmacy. Methods: This narrative review presents the current knowledge on the pharmacology, efficacy, and safety of topical drugs used in pain treatment. Particular attention is given to topical non-steroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, menthol, and camphor. The review also discusses newer and less established therapies used mainly in neuropathic pain, including topical ketamine, amitriptyline, phenytoin, gabapentin, and clonidine. A structured, non-systematic literature search was conducted using the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases to identify studies evaluating the efficacy and safety of topical analgesic therapies. Results: Current evidence supports topical NSAIDs as first-line therapy for localized musculoskeletal pain and osteoarthritis, while lidocaine and high-concentration capsaicin patches are effective options in focal neuropathic pain. Although several newer topical therapies show promising results, more high-quality clinical studies are still needed. Overall, topical analgesia is an important part of multimodal pain management because it combines analgesic efficacy with a better safety profile compared with many systemic therapies. Conclusions: Taking the aspects discussed in this paper into account, it seems justified to search for new drug combinations that would contribute to effective pain therapy with topical agents. It is recognized that a multimodal approach to pain management, which utilizes drugs with different mechanisms of action, can increase efficacy and reduce the systemic adverse events of the drugs used. The effective and safe treatment of patients with pain, especially neuropathic pain, despite emerging new clinical trials, remains a challenge for clinicians.
Angiogenesis, the growth of vasculature from existing blood vessels, requires the coordinated secretion of multiple angiogenic growth factors that each stimulate the cellular recruitment, patterning, and morphogenesis inherent to vascular network formation. Among these secreted factors, vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and platelet derived growth factor (PDGF) amplify key stages of angiogenesis. Disruptions in their secretion have been implicated in poor vascular network formation. Current methods for exploring variations in the phased presentation of multiple different proteins are limited, which has restricted our ability to explore the effect of growth factor timing on angiogenesis. To address this knowledge gap, we developed affibodies, which are alpha-helical binding proteins, to phase the release of VEGF-165, FGF-2, and PDGF-BB from a single delivery vehicle via specific protein-affibody affinity interactions. We used yeast surface display to engineer three VEGF-, three FGF-2-, and two PDGF-specific affibodies with a wide range of affinities for their target proteins spanning dissociation constants of 3.08 ± 0.21 nM to 4550 ± 590 nM. We demonstrated that the cumulative release of VEGF and FGF-2 is inversely correlated with the strength of the protein-affibody affinity interaction and that hydrogels containing multiple protein-specific affibodies can control the release of VEGF, FGF-2, and PDGF, largely in accordance with the strength of the affinity interactions. Using a rat-derived intact microvascular fragment (MVF) model of in vitro angiogenesis, we revealed that sequential delivery of soluble VEGF, followed by FGF-2, and then PDGF enhances vascular network length by 2.8-fold and branching by 4.1-fold compared to untreated MVFs. We then designed an affibody-conjugated polyethylene glycol maleimide (PEG-MAL) hydrogel to mimic this sequence of protein delivery, resulting in a 3.0-fold increase in vascular network length and a 2.3-fold increase in vascular branching compared to all other hydrogel compositions and the sequential delivery of soluble growth factors. Changing temporal growth factor presentation with affibody-conjugated hydrogels altered the expression of key angiogenic genes involved in vessel stabilization and destabilization and matrix remodeling. Perivascular coverage measured by the colocalization of lectin and alpha smooth muscle actin staining was similar between all treatment groups, suggesting pericyte recruitment to stabilize expanded vascular networks created by the soluble and affibody-mediated delivery of the optimal sequence of proteins. Overall, this work establishes a new biomaterial platform for modulating the timing of growth factor delivery, enabling the exploration of how temporal variations in protein secretion impact regeneration and development.
The current investigation aims to fabricate, optimize and characterize dual-drug-loaded liposomes for the management of colon cancer.Significance: Lipid-based nanocarriers are versatile nanocarriers that facilitate the loading of both hydrophilic and hydrophobic therapeutic agents. The simultaneous delivery of capecitabine (CAP) and celecoxib (CEL) is anticipated to enhance anticancer efficacy against colon cancer. CAP-CEL-loaded liposomes (CAP-CEL-LIPs) were designed and optimized utilizing Box-Behnken Design (BBD). The optimized LIPs were characterized for particle size, polydispersity index (PDI), entrapment efficiency and morphological studies. In vitro drug release studies were conducted under both acidic and physiological conditions. Hemocompatibility was evaluated using the hemolysis assay and the stability of the LIPs was assessed over a duration of one month. ResultsThe optimized CAP-CEL-LIPs demonstrated a mean particle size of 130 ± 2.36 nm with a PDI of 0.162 ± 0.008, showing the homogeneous particle size distribution. The encapsulation efficiency for CAP and CEL was found to be 64.96 ± 2.81% and 92.23 ± 2.22%, respectively. SEM and TEM images revealed the spherical morphology of the developed LIPs. In vitro drug release investigations revealed a controlled release profile for both drugs under both acidic and physiological conditions. The hemolysis assay showed hemolysis rate of less than 2%, thereby confirming superior blood compatibility. Stability data indicated that LIPs remained stable for one-month. The developed CAP-CEL-LIPs showed significant cytotoxic potential with enhanced cellular uptake and apoptotic activity against colon cancer cells. The engineered CAP-CEL-LIPs could be a promising platform for managing colon cancer.
Advances in fetal diagnosis and molecular medicine have opened new opportunities for in utero molecular-targeted drug therapy, shifting fetal treatment from purely procedural interventions toward pharmacologic strategies that address disease mechanisms before irreversible organ damage occurs. In this review, we highlight recent advances in in utero drug therapy, focusing on molecular-targeted approaches with emerging clinical or trial-level evidence. Early clinical experience and ongoing trials have demonstrated the feasibility of achieving therapeutically relevant fetal drug exposure, although the strength of evidence varies considerably across therapeutic classes. However, significant challenges remain, including optimization of fetal drug delivery, characterization of fetal pharmacokinetics and pharmacodynamics, long-term safety assessment, and ethical considerations. The current evidence base ranges from single case reports to ongoing Phase 3 clinical trials, underscoring both the promise of prenatal molecular therapeutics and the need for further prospective evaluation. Continued integration of fetal imaging, genomics, ethics and pharmacology will be essential to advance safe and effective prenatal precision therapies.
Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide, highlighting the need for safer and more effective chemopreventive strategies. Although many phytochemicals can modulate key molecular processes involved in breast carcinogenesis, their chemopreventive potential largely depends on delivery strategies that preserve their biological activity and enable efficient accumulation at the target site. Protein-based nanocarriers have emerged as promising delivery systems capable of improving the protection, solubility, cellular uptake, targeted delivery, and controlled release of bioactive compounds in tumor tissues. This review summarizes recent advances in selected animal- and plant-derived protein nanocarriers used for the encapsulation and delivery of natural compounds in breast cancer chemoprevention. Particular attention is given to their physicochemical properties, encapsulation performance, release behavior, biological activity, targeting potential, and translational limitations. Furthermore, the mechanisms underlying the enhanced anticancer activity of encapsulated phytochemicals, including improved stability, receptor-mediated uptake, pH-responsive release, apoptosis induction, oxidative stress modulation, and inhibition of tumor growth and metastasis, are highlighted. Current challenges, including enzymatic degradation, formulation instability, immunogenicity concerns, manufacturing scalability, and limited clinical evidence, remain important barriers to translation. Overall, selected protein-based nanocarriers represent promising multifunctional platforms for improving the chemopreventive potential of natural compounds in breast cancer.
Oral cancer, particularly oral squamous cell carcinoma, represents a major global health challenge with high rates of morbidity and mortality. Current treatments often encounter limitations such as toxicity and drug resistance. Curcumin, a natural polyphenol derived from turmeric, has shown significant promise as a therapeutic agent due to its anti-inflammatory, antioxidant, and broad-spectrum anticancer activities. However, its clinical application has been limited by poor solubility, rapid metabolism, and low bioavailability. This review examines the potential of novel curcumin formulations developed to address these challenges in oral cancer treatment. It explores advanced delivery systems including nanoparticle-based carriers, liposomes, niosomes, and hybrid technologies that enhance bioavailability and enable targeted delivery. Additionally, the review discusses synthetic curcumin analogues that offer improved stability and potency. These innovative approaches demonstrate enhanced anticancer effects through pro-apoptotic, anti-proliferative, and anti-angiogenic mechanisms, often exhibiting synergistic activity with conventional therapies. This review aims to synthesize current evidence on the mechanisms and efficacy of these advanced curcumin-based strategies and provide future perspectives on their role as safe and effective options in oral oncology.
Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with current treatments often limited by drug resistance and systemic toxicity. Although traditional Chinese medicine components such as Astragaloside IV and polypeptide extract from scorpion venom (PESV) have demonstrated promising antitumor activity, their clinical translation is hampered by poor bioavailability and lack of tumor specificity. To address these limitations, we engineered an E3 aptamer-modified T cell-derived exosomal nanoplatform (EAPE) for the targeted co-delivery of Astragaloside IV and PESV in prostate cancer therapy. EAPE was constructed and characterized, and its targeting capability, biosafety, and therapeutic performance were evaluated in vitro and in vivo. In vitro, the antitumor efficacy was assessed by proliferation, migration and apoptosis assays, while the immunomodulatory effects were investigated using a co-culture system of LNCaP cells and T lymphocytes. In vivo, the antitumor efficacy and immune activation were examined in prostate cancer xenograft mouse model, with tumor growth inhibition, apoptosis and immune responses measured. EAPE demonstrated efficient tumor-targeting capability and favorable biosafety profiles both in vitro and in vivo. EAPE demonstrated superior therapeutic efficacy against PCa by inhibiting proliferation and migration of prostate cancer cells and inducing apoptosis, while suppressing immunosuppression and activating antitumor immune response. This study presents a biologically derived, targeted nanodelivery system that improves the delivery efficiency and therapeutic efficacy of Astragaloside IV and PESV. These findings support the potential of exosome-based nanoplatforms as promising strategies for enhancing the translational application of traditional Chinese medicine-derived therapeutics in prostate cancer.
Nucleic acid therapeutics, including oligonucleotides, messenger RNA and DNA, are promising drug modalities for treating various diseases. However, despite their increasing impact on medicine, their precise and efficient delivery remains a considerable challenge. Dendrimers, recognized by their uniquely branched architecture and precise structures in concert with cooperative multivalency, are a platform for targeted and precise delivery of nucleic acid therapeutics. Here we review state-of-the-art engineering of dendrimers pertaining to nucleic acid delivery, highlighting progress made in their design and functional mechanization for delivering different types of nucleic acids for therapeutic applications. We also discuss challenges including manufacturing, safety and regulatory issues associated with their clinical applications. Finally, we conclude by offering our perspective on dendrimer engineering that are expected to overcome current obstacles for advancing nucleic acid therapeutics development.
Oligonucleotide therapeutics are becoming representatives of the "Third Wave" of pharmaceutical innovation, expending from initial rare diseases to oncology and chronic indications, following small molecules and proteins. Globally, hundreds of clinical trials are currently underway, in addition to the 26 oligonucleotide drugs that have already been approved. Although nearly thirty years have elapsed since the initial approval of Fomivirsen, oligonucleotide therapeutics continue to pose unique CMC (Chemistry, Manufacturing, and Controls) challenges that are distinct from small molecules. Furthermore, the lack of harmonized ICH guidelines specifically for oligonucleotides forces developers to navigate a "regulatory grey area" between new molecular entities (NMEs) and biologics. This perspective focuses on the technical and regulatory hurdles of API (Active Pharmaceutical Ingredient) CMC development, covering synthesis (including conjugation strategies with delivery systems), analysis and regulatory aspects, with a specific emphasis on stage-appropriate requirements from the Investigational New Drug (IND) application to the New Drug Application (NDA).
Bladder preservation has emerged as an established treatment option for selected patients with muscle-invasive bladder cancer (MIBC), offering durable oncologic control with the potential to maintain native bladder function and quality of life. Over the past several decades, prospective trials and large institutional experiences have refined trimodality therapy (TMT)-maximal transurethral resection followed by definitive radiation therapy with concurrent radiosensitizing systemic therapy-and clarified principles of patient selection, treatment delivery, surveillance, and salvage. Randomized evidence supports combined-modality therapy as the backbone of bladder preservation, and contemporary comparative analyses suggest outcomes comparable to radical cystectomy in appropriately selected populations. This review synthesizes the clinical foundations of bladder preservation, including radiobiologic considerations, advances in radiation technique, and patterns of recurrence following TMT. We discuss outcomes in higher-risk populations, including locally advanced and node-positive disease, and examine the evolving integration of systemic therapies. The emergence of immune checkpoint inhibitors and antibody-drug conjugates in urothelial carcinoma has reshaped the systemic treatment landscape and raises important questions regarding patient selection, sequencing, and the potential expansion of organ-preserving strategies. Finally, we outline future directions-including response-adaptive approaches, advances in image-guided and adaptive radiotherapy, and ctDNA-enabled risk stratification-while emphasizing the need for prospective validation and multidisciplinary collaboration to refine and optimize bladder-preserving care.
Current treatments for pancreatic ductal adenocarcinoma (PDAC) patients are typically restricted to (neo)adjuvant chemotherapy, surgery or palliative care. Mainly due to a late diagnosis and highly desmoplastic environment, these treatments have limited efficacy and patient prognosis is very poor. Intratumoral delivery of chemotherapeutic agents using hydrogel technology might boost treatment efficacy and reduce side effects. Here, we aimed to investigate the preclinical efficacy and tolerability of a novel thermosensitive hydrogel, ChemoGell, loaded with the chemotherapeutic agent gemcitabine. We explored this in vitro, using patient-derived organoids and surgically obtained tumor explants, and in vivo, using a human patient-derived xenograft (PDX) and syngeneic KPC3 mouse models. Upon intratumoral injections of gemcitabine-loaded ChemoGell, respective survival, peripheral blood and end-stage tumor histological analyses were performed. Intratumoral injection of gemcitabine-loaded ChemoGell in in vitro and in vivo models showed decreased tumor growth and increased cytotoxicity compared to blank ChemoGell and saline control intratumoral injections. In contrast, systemic administration of gemcitabine did not show therapeutic benefits. Intratumoral ChemoGell injections induced interesting lymphocyte and monocyte dynamics overtime, showing an intratumoral influx of NK cells and monocytes and an in-depot infiltration of activated fibroblasts, macrophages and activated CD8 + T cells. Our findings establish a foundation for integrating localized treatment modalities, addressing critical challenges in PDAC and improving patient prognosis through more effective, localized therapeutic strategies.
Despite the growing importance of lipid nanoparticles (LNPs) in mRNA therapeutics, current ionizable lipids, which comprise an ionizable head group, a linker, and hydrophobic tails that collectively govern the delivery behavior, exhibit dose-limiting toxicity and suboptimal efficiency. Hydrophobic tail chemistry has been implicated in these limitations; however, a systematic structure-activity relationship (SAR) analysis is lacking. In this study, the authors synthesized a 56-member library of tail-modified ionizable lipids with biodegradable disulfide linkages and variations in chain length and branching. Systematic SAR evaluation revealed that hydrophobic tail architecture critically determines endosomal escape, biocompatibility, and mRNA translation efficiency. Optimized LNPs delivered mRNA with potent efficacy and markedly reduced cytotoxicity, lower cytokine induction, and balanced Th1/Th2 immune activation in a nonhuman primate model. The findings establish the first comprehensive SAR framework linking tail chemistry to ionizable lipid function, offering molecular design principles for next-generation LNPs and enabling the development of safer and more effective mRNA-based vaccines and therapeutics.
Rapid precorneal clearance remains a major limitation of topical ocular therapy, yet the fundamental physical mechanisms governing particle retention under tear flow are poorly understood. Current delivery strategies primarily rely on empirical optimization of surface chemistry, while the role of particle size in interfacial stability under dynamic conditions remains largely unexplored. Here, we establish a mechanistic size-retention-pharmacodynamic framework for porous vaterite particles designed as mucoadhesive ocular drug carriers. Two structurally equivalent particle fractions were engineered: micron-sized (3.8 ± 0.5 µm) and submicron (0.65 ± 0.15 µm) particles with preserved vaterite phase stability in simulated tear fluid, porous architecture, comparable surface physicochemical properties, matched enalaprilat loading (∼5 wt%), and diffusion-controlled release kinetics. This design enabled isolation of particle size as the primary variable governing interfacial behavior. Under tear-mimicking flow on mucin-coated substrates, submicron particles exhibited ∼1.8-fold slower washout compared to micron-sized counterparts. This difference is consistent with a size-dependent balance between hydrodynamic torque and adhesive stabilization, where detachment propensity increases with particle diameter. Ex vivo corneal experiments under ∼100 × accelerated physiological tear flow revealed convergence of retention (∼10% surface coverage after 2 h), indicating a transition from physics-dominated to biology-dominated interfacial behavior on native tissue. Most importantly, these interfacial effects were associated with improved therapeutic performance in vivo. Submicron enalaprilat-loaded particles produced a more sustained intraocular pressure reduction and an approximately 2.1-fold increase in cumulative intraocular pressure-lowering effect compared to free drug, whereas micron-sized particles showed no clear improvement. Developed formulations demonstrated good cytocompatibility and excellent ocular tolerability in vitro and in vivo. Overall, this work identifies particle size as a key parameter of interfacial retention under flow and suggests that reducing hydrodynamic detachment at mucosal interfaces can enhance ocular pharmacodynamic performance without increasing the administered drug dose. The presented framework provides a basis for rational design of interface-controlled drug delivery systems beyond empirical formulation approaches.
Cutaneous leishmaniasis (CL) remains a major global health challenge, particularly in low- and middle-income countries, due to the limitations of current therapies, including toxicity, high cost, invasive administration routes, and poor patient adherence. In this context, nanotechnology-based drug delivery systems, such as nanofibers, have emerged as promising alternatives to improve therapeutic outcomes. This study provides a comprehensive overview of CL, its epidemiology, clinical manifestations, and current pharmacological treatments, followed by a systematic and critical analysis of nanofiber-based platforms for its treatment. A structured search was conducted in PubMed, Web of Science, and Scopus databases, covering studies published between 2010 and 2026. Seventeen studies met the inclusion criteria and were analyzed in terms of polymer composition, fabrication techniques, physicochemical properties, and biological performance. The results demonstrated that polymeric nanofibers, particularly those produced by electrospinning and solution blow spinning, exhibit favorable characteristics, including high surface area, controlled drug release, biocompatibility, and enhanced local drug retention. Both in vitro and in vivo studies revealed significant antileishmanial activity, reduced cytotoxicity, and improved wound healing. Additionally, preliminary clinical findings highlighted their potential as safe and non-invasive therapeutic alternatives. Complementary bibliometric and patent analyses indicated increasing scientific and technological interest in this field, while highlighting key translational challenges related to standardization, scalability, regulatory approval, and clinical validation. Overall, nanofiber-based systems represent a promising translational strategy for the topical treatment of CL, offering advantages over conventional therapies and addressing key challenges associated with current clinical management.