Curcumin, a natural polyphenol derived from Curcuma longa, exhibits potent multimodal anticancer activity by modulating critical oncogenic pathways (e.g., NF-κB, STAT3, PI3K/Akt/mTOR), inducing apoptosis, suppressing angiogenesis, and reversing multidrug resistance (MDR). However, its clinical translation is severely hindered by poor aqueous solubility, rapid metabolism, and negligible oral bioavailability (typically <1% in serum), which result in subtherapeutic concentrations at tumor sites. Smart nanoparticle delivery systems have emerged as a transformative strategy to overcome these limitations, enabling enhanced solubility, controlled release, and targeted accumulation in tumors. This review comprehensively summarizes the advancements in curcumin-loaded nanocarriers, including polymeric nanoparticles (e.g., PLGA, chitosan), lipid-based systems (e.g., liposomes, NLCs), inorganic nanoparticles (e.g., mesoporous silica, gold nanoparticles), and stimuli-responsive platforms (pH-, redox-, enzyme-sensitive). These nanosystems leverage passive targeting via the enhanced permeability and retention (EPR) effect and active targeting through ligand conjugation (e.g., folate, transferrin, hyaluronic acid), significantly improving tumor-specific delivery and curcumin's bioavailability-exemplified by a 178-fold increase in plasma AUC in healthy human volunteers following oral administration of the co-grinding formulation CUMINUP60® compared to standard crystalline curcumin. Preclinical and clinical studies demonstrate that nanoformulated curcumin synergizes with conventional chemo/radiotherapy, sensitizes resistant cancers, and modulates the immunosuppressive tumor microenvironment. For instance, Phase I/II trials indicate that formulations like nanomicellar curcumin (Sinacurcumin®) can modulate inflammatory cytokines, while liposomal variants (Lipocur™) have shown target engagement in metastatic cancers, albeit with the need for dose optimization. Hybrid nanocarriers co-delivering curcumin with chemotherapeutics or siRNA further augment therapeutic outcomes in models of colorectal, breast, pancreatic, and glioblastoma cancers. Despite these progresses, the gap between preclinical success and clinical translation remains significant. This review critically analyzes the barriers impeding commercialization, specifically highlighting the heterogeneity of the EPR effect, the lack of scalable GMP-compliant manufacturing for complex nanocarriers, and the regulatory hurdles regarding long-term biocompatibility and safety assessments.

Background: Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited treatment options. Premature senescence of alveolar epithelial type II cells (AT2 cells) plays a critical role in PF pathogenesis. This study aimed to identify natural compounds targeting senescence-related pathways for PF treatment. Methods: An integrated approach was implemented, combining bioinformatics, artificial intelligence (AI)-assisted molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, and experimental validation. Core targets associated with aging-related pulmonary fibrosis (PF) were identified via database mining (GeneCards and AgingAtlas) and protein-protein interaction (PPI) network analysis. Natural compounds were screened using the HERB database, and resveratrol (RES) was selected due to its multi-target activity and favorable ADMET characteristics. The efficacy of RES was evaluated through in vitro experiments using bleomycin (BLM)-induced senescent A549 alveolar epithelial cells and in vivo studies in a BLM-induced PF mouse model (C57BL/6J). Molecular docking simulations were performed to predict the binding affinity between RES and key targets, including SERPINE1, MMP2, and IL-6. Results: Bioinformatics identified 322 aging-related PF targets, with TP53, AKT1, STAT3, JUN, and NFKB1 as core regulators. Resveratrol was selected as a top candidate modulating all five core targets and exhibiting optimal drug-likeness. Molecular docking and dynamics simulations confirmed strong binding affinity between RES and key senescence-associated proteins (SERPINE1: −8 kcal/mol; MMP2: −7.5 kcal/mol; IL-6: −7.1 kcal/mol). In vitro , RES (10–40 μM) significantly suppressed bleomycin-induced senescence in A549 cells, reducing SA-β-Gal activity and downregulating SERPINE1, MMP2, and IL6 expression. In vivo , RES treatment (20–80 mg/kg, 21 days) attenuated bleomycin-induced PF in mice, improving weight loss, reducing alveolar damage, inflammation, and collagen deposition (Masson’s trichrome) in a dose-dependent manner. Conclusion: Resveratrol effectively inhibits alveolar epithelial cell senescence and ameliorates pulmonary fibrosis, likely by targeting key senescence-associated pathways (e.g., SERPINE1, MMP2, IL-6). This study provides a promising transdisciplinary strategy for anti-fibrotic drug discovery and highlights RES as a potential therapeutic candidate for PF.

Resveratrol (RSV), a natural polyphenol with multifaceted anticancer mechanisms, faces significant pharmacokinetic challenges that limit its clinical utility. This review explores the synergistic integration of RSV with hydrogel-based delivery systems to overcome these limitations and enhance therapeutic efficacy in cancer treatment. Hydrogels, renowned for their tunable physicochemical properties and stimuli-responsive behavior, enable precise spatiotemporal control over RSV release, improving stability, bioavailability, and tumor-targeted delivery. Compared to alternative delivery systems (e.g., liposomes, polymeric nanoparticles), RSV-loaded hydrogels offer distinct advantages in sustained local release and microenvironmental modulation. Advanced hydrogel designs, including pH- and temperature-responsive systems, nanocomposites, and self-healing networks, further amplify RSV’s bioactivity by sustaining therapeutic concentrations, modulating tumor microenvironments, and synergizing with chemo-photothermal or immunotherapeutic strategies. Preclinical applications in colorectal cancer and glioblastoma demonstrate RSV-hydrogel platforms’ ability to suppress metastasis, reverse chemoresistance, and eradicate cancer stem cells through mechanisms such as Wnt/β-catenin inhibition and ROS-triggered drug activation. While these preclinical results are promising, significant translational challenges remain, including scalable manufacturing, biocompatibility, and clinical translation. Future research priorities include developing more sophisticated stimuli-responsive systems and exploring potential synergies with emerging therapeutic modalities to bridge the gap towards clinical application.

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.