Sepsis-induced liver failure remains a serious and often under-recognized complication of abdominal sepsis. Clinical reports suggest that liver dysfunction develops in a substantial proportion of these patients, and once failure ensues, mortality rises sharply. Despite progress in antimicrobial therapy and critical care support, there is still no therapy that directly halts or reliably reverses septic liver injury. Systemic drug administration frequently underperforms in this setting. Hepatic drug accumulation becomes unpredictable, pharmacokinetics shift, and immune dysregulation further complicates therapeutic control. Nanotechnology-based delivery systems have attempted to address these shortcomings by improving drug stability and circulation time. Yet their behavior under septic conditions remains inconsistent. This inconsistency may reflect a deeper issue: most carriers are engineered under relatively stable physiological assumptions that do not hold during systemic inflammation. Biomimetic platforms, particularly those derived from erythrocyte membranes, offer a different conceptual entry point. Rather than merely evading immune recognition, erythrocyte-based systems interact naturally with hepatic clearance pathways. During sepsis, erythrocyte turnover appears to accelerate, and macrophage-mediated clearance in the liver intensifies. This shift, while pathologic, may present a therapeutic opportunity. In this review, we examine current liver-targeted delivery strategies for sepsis-induced liver failure and critically assess the underexplored role of erythrocyte ghost-based systems. We discuss how sepsis-specific pathophysiological changes reshape carrier biodistribution, identify translational constraints, and propose design considerations for inflammation-adaptive biomimetic platforms. By reconsidering hepatic clearance not solely as a pharmacokinetic barrier but as a potential delivery route, we outline a disease-aligned approach to nanomedicine design in septic organ failure.

Background/Objectives: Ceftriaxone (Ctx) is a third-generation cephalosporin widely used to treat infections caused by Gram-positive and Gram-negative bacteria. However, its clinical efficacy may be limited by rapid systemic elimination and suboptimal tissue distribution. Erythrocyte-based targeted drug delivery systems (TDDSs) have emerged as a promising approach to prolong drug circulation and enhance site-specific accumulation. This study investigated the pharmacokinetic profile and tissue distribution of ceftriaxone encapsulated in autologous erythrocytes (RBC-Ctx) compared with free ceftriaxone (Free-Ctx) following intravenous administration in rats. Methods: Ceftriaxone was encapsulated into autologous rat erythrocytes using a hypoosmotic hemolysis loading technique. Drug-loaded erythrocytes are called pharmacocytes. Adult male Wistar rats received a single intravenous injection of Free-Ctx or RBC-Ctx at an equivalent ceftriaxone dose of 340 mg/kg. Plasma samples were collected over 24 h for pharmacokinetic analysis, while the liver, spleen, lungs, kidneys, heart, pancreas, and skeletal muscle were harvested at 1 and 12 h for tissue distribution studies. Ceftriaxone concentrations were quantified by high-performance liquid chromatography with UV detection. Results: Erythrocyte encapsulation significantly modified the pharmacokinetic behavior of ceftriaxone. Compared with Free-Ctx, RBC-Ctx prolonged the elimination half-life (4.4 ± 0.6 vs. 1.8 ± 0.1 h), increased systemic exposure (AUC₀–last, 1.6 ± 0.1 vs. 1.2 ± 0.2 mg·h/mL), reduced total body clearance (218.2 ± 11.0 vs. 294.0 ± 48.8 mL/h/kg), and increased the apparent volume of distribution at steady state (688.3 ± 61.0 vs. 435.0 ± 23.1 mL/kg). In addition, RBC-Ctx was associated with a distinct relative tissue-distribution pattern of ceftriaxone, particularly in reticuloendothelial system-rich organs such as the liver and spleen, while ceftriaxone remained detectable in several tissues at 12 h after administration. In contrast, ceftriaxone concentrations following Free-Ctx declined markedly or became undetectable over the same period. Conclusions: Encapsulation of ceftriaxone into autologous erythrocytes substantially prolonged systemic circulation, enhanced drug exposure, reduced clearance, and altered the relative tissue distribution of ceftriaxone. These findings demonstrate that erythrocyte-based carriers effectively modulate ceftriaxone pharmacokinetics and tissue distribution, supporting their potential as a targeted antibiotic delivery platform for improving antimicrobial therapy, particularly for infections involving reticuloendothelial system-associated tissues. Further studies in experimental models of infection and inflammation are warranted to evaluate therapeutic efficacy under pathological conditions and to optimize this delivery strategy.

Background/Objectives: Diabetic foot ulcers are characterized by persistent inflammation, impaired angiogenesis, and delayed tissue regeneration. Epidermal growth factor (EGF) is an important regulator of wound repair; however, its therapeutic application may be limited by rapid degradation and poor retention within the wound environment. This study investigated the therapeutic efficacy of local administration of EGF and ceftriaxone using autologous red blood cell-derived carriers (RBCDCs) in an experimental model of diabetic wound healing in rats. Methods: Experiments were conducted on 30 albino Wistar rats (250 ± 20 g) with experimentally induced diabetic wounds. In the RBCDC treatment groups, separately prepared drug-loaded RBCDC formulations containing EGF or ceftriaxone were locally administered into the wound. The corresponding comparison groups received the same active agents in free form according to an identical treatment schedule, while an additional control group received topical Levomekol. Results: RBCDC-mediated administration of EGF and ceftriaxone significantly accelerated wound closure and was associated with earlier resolution of inflammation, granulation tissue maturation, re-epithelialization, collagen deposition, and angiogenesis compared with the corresponding free-drug formulations. On day 9, tissue EGF concentration was higher in the RBCDC (EGF + Ctx) group than in the corresponding free-drug group. Additional formulation characterization demonstrated ceftriaxone encapsulation and in vitro release from RBCDCs, as well as in vitro EGF release from EGF-loaded RBCDCs. Conclusions: Autologous RBCDCs represent a promising local drug-carrier platform for the administration of regenerative and antimicrobial agents in experimental diabetic wounds. Further studies are required to establish local pharmacokinetics, systemic exposure, carrier stability, and the mechanisms responsible for the observed therapeutic effects.

Background/Objectives: Acute pancreatitis (AP) is a common inflammatory disorder associated with substantial morbidity, mortality, and healthcare burden, particularly in patients with systemic inflammatory response syndrome (SIRS), pancreatic necrosis, and multiple organ dysfunction syndrome (MODS). Despite advances in intensive care management, nutritional support, and minimally invasive interventions, effective pharmacological therapies targeting the underlying inflammatory and enzymatic mechanisms remain limited. Protease activation, excessive inflammation, and immune dysregulation are key drivers of AP progression. Ulinastatin, a broad-spectrum serine protease inhibitor, exerts anti-inflammatory, antioxidant, and organ-protective effects by modulating protease activity, NF-κB signaling, cytokine production, and inflammasome activation. However, conventional intravenous administration is limited by rapid systemic clearance, nonspecific distribution, and insufficient drug exposure at sites of pancreatic inflammation, necessitating repeated dosing. This narrative review aims to evaluate the scientific rationale and the therapeutic potential of ulinastatin-loaded erythrocyte-based drug delivery systems as an innovative strategy for improving the efficacy of acute pancreatitis therapy by optimizing the sustained anti-inflammatory effect of ulinastatin in foci of pancreatic inflammation. Methods: Qualitative narrative synthesis of relevant experimental and clinical literature on AP pathogenesis, ulinastatin pharmacology and therapy, protease inhibition, erythrocyte ghosts, erythrocyte pharmacocytes, and erythrocyte-based drug delivery systems was critically reviewed. The analysis focused on evidence relevant to pancreatic inflammation, drug-delivery performance, potential therapeutic benefits, and translational limitations. Results: Available evidence supports the pharmacological relevance of ulinastatin in inflammatory and protease-mediated conditions and identifies erythrocyte-derived carriers as a potential platform for drug encapsulation, prolonged circulation, and controlled drug release. Direct experimental studies investigating ulinastatin-loaded erythrocyte pharmacocytes in AP are currently lacking. Conclusions: By combining the pharmacological properties of ulinastatin with the physiological advantages of erythrocyte-mediated drug delivery, this approach may offer potential therapeutic benefits. However, these potential advantages remain hypothetical and require validation through dedicated pharmaceutical characterization, pharmacokinetic, biodistribution, and efficacy studies. Ulinastatin-loaded erythrocyte pharmacocytes represent a scientifically plausible but currently unvalidated drug delivery strategy for AP. This narrative review critically examines the therapeutic rationale for combining ulinastatin with erythrocyte-derived drug carriers as a potential targeted delivery strategy for acute pancreatitis. It synthesizes relevant evidence on ulinastatin pharmacology, erythrocyte-based drug delivery, inflammatory mechanisms, and the limitations of conventional systemic administration. Particular attention is given to the potential advantages, translational challenges, and key research gaps associated with this proposed approach. Further preclinical studies are warranted to comprehensively evaluate their pharmacokinetic properties, biological activity, safety, therapeutic efficacy, and potential for clinical translation.