Siyuan Chen

Background: Effective topical management of sensitive skin remains challenging because inadequate cutaneous delivery limits the therapeutic performance of many anti-inflammatory agents. Glycyrrhetinic acid (GA) possesses well-recognized anti-inflammatory and barrier-protective activities, yet its clinical potential is constrained by poor aqueous solubility and inefficient skin delivery. This study aimed to develop a hyaluronic acid (HA)-engineered ethosomal system to enhance the local delivery and therapeutic efficacy of GA for sensitive skin. Methods: HA-coated GA-loaded ethosomes (HAGA-ETs) were prepared by electrostatic adsorption of HA onto a cationic ethosomal template. The physicochemical properties, release behavior, storage stability, skin retention, cellular uptake, and biological activities of HAGA-ETs were systematically evaluated using TNF-α/IFN-γ-stimulated HaCaT cells and an SLS-induced 3D reconstructed skin model. Results: HAGA-ETs exhibited a mean particle size of 140.1 nm, encapsulation efficiency exceeding 95%, sustained drug release, and good storage stability. Compared with Free-GA and unmodified ethosomes, HAGA-ETs showed improved cytocompatibility, enhanced skin retention, greater keratinocyte uptake, and stronger anti-inflammatory activity. HA pre-saturation attenuated the enhanced cellular uptake of HAGA-ETs, supporting the involvement of HA receptor-mediated cellular interaction. HAGA-ETs also more effectively restored barrier-related markers, suppressed hyper-reactivity- and allergy-associated mediators, and inhibited the activation of MAPK/NF-κB, JAK1/STAT1, and TRPV1-related signaling pathways in both cellular and 3D skin models. Conclusions: HA surface engineering effectively improved the topical delivery and local therapeutic efficacy of GA by enhancing skin retention and keratinocyte interaction. HAGA-ETs represent a promising nanoplatform for the local management of sensitive skin.

Hyperpigmentation treatment with tranexamic acid (TA) is limited by poor skin penetration and insufficient local retention resulting from its hydrophilic nature. In this study, a detachable bilayer microneedle system loaded with TA liposomes (TA-LIP MNs) was developed to improve localized skin delivery and sustained retention of TA. TA-loaded liposomes (TA-LIP) were prepared by thin-film hydration and incorporated into silk fibroin (SF)-based microneedle tips, while hyaluronic acid was used as a rapidly dissolving base layer. The optimized TA-LIP exhibited a uniform nanosized distribution (~100 nm) and favorable storage stability. TA-LIP MNs possessed sufficient mechanical strength for skin insertion and achieved complete tip-base separation within 3 min after insertion into mouse skin. Confocal imaging demonstrated that liposomal payloads reached a skin depth of approximately 320 μm, indicating efficient delivery to melanocyte-rich epidermal and superficial dermal regions. Compared with free TA solution, TA-LIP MNs increased TA permeation by 4.94-fold and significantly enhanced skin retention after 24 h. The enhanced delivery behavior was associated with the synergistic effect of microneedle-created microchannels and liposomal diffusion within skin tissue. In vitro studies further demonstrated that TA-LIP MNs maintained favorable biocompatibility, enhanced cellular uptake, inhibited melanin synthesis and tyrosinase activity in α-MSH-stimulated B16 cells, and reduced intracellular ROS levels in H₂O₂-induced HaCaT cells. Collectively, the detachable bilayer TA-LIP MNs combined rapid tip separation, enhanced skin retention, and sustained liposomal delivery, resulting in improved antimelanogenic and antioxidant activities. This platform represents a promising skin delivery strategy for the management of hyperpigmentation.

Background: Effective anti-aging requires dual strategies to stimulate regeneration and counteract damage. While the combination of hydroxypinacolone retinoate (HPR) and carnosine (CA) holds great promise, their effectiveness is hampered by instability and poor skin penetration. Methods: To overcome these challenges, this study developed HPR and CA co-encapsulated nanoliposomes (HC-NLPs) via high-pressure homogenization as an advanced epidermal/dermal delivery system. Results: HC-NLPs markedly improved skin retention of HPR (58.97%) and CA (111.36%) compared to the free combination (Free-HC). In cellular studies, HC-NLPs displayed excellent biocompatibility and demonstrated a 4.7-fold higher cellular uptake. This led to enhanced proliferative (EdU positive rate increased by 78.32%) and migratory (wound closure improved by 31.5%) capacities. Moreover, HC-NLPs effectively reinforced multiple skin-protective processes associated with aging, including enhanced resistance to oxidative and glycation-induced damage, suppressed inflammatory responses, and strengthened cellular barrier integrity. In 3D skin models, HC-NLPs promoted collagen deposition and improved tissue morphology compared to Free-HC. Their superior in vivo antioxidant and anti-aging effects were further validated in Zebrafish assays. HC-NLPs effectively co-deliver HPR and CA, markedly improving their stability, skin penetration, and cellular internalization. Conclusions: The formulation demonstrates comprehensive pro-regenerative, anti-inflammatory, antioxidative, and anti-glycation effects, representing a promising nano-delivery strategy for advanced anti-aging skincare.

Oral administration remains the most patient-friendly drug delivery route, yet its efficacy is limited by physiological barriers including gastric degradation and inefficient cellular uptake. pH-responsive nanogels have shown promise for gastrointestinal drug delivery, though their effectiveness is often constrained by poor membrane interaction. Inspired by natural membrane-anchoring mechanisms, a series of comb-like anionic polymers were designed via grafting alkylamines of different chain lengths (C₁₀, C₁₄, C₁₈) at varying densities (10–30%) onto a biodegradable poly(L-lysine isophthalamide) (PLP) backbone. These pH-responsive comb-like polymers self-assembled into nanogels for loading the hydrophobic chemotherapeutic agent camptothecin. The alkyl length and grafting density significantly influenced pH-responsive behavior, membrane disruption, and drug release profiles. The optimal formulation—the nanogel prepared with PLP grafted 30% C₁₄—achieved a high drug-loading capacity, ideal particle size and stability, and offered superior protection in acidic conditions (only 7 ± 5% release at pH 1.2 over 24 h), while enabling rapid intestinal release (78 ± 2% at pH 7.4 within 24 h). The nanogels significantly enhanced cellular uptake, cytoplasmic delivery, and cytotoxicity against colorectal carcinoma cells. This study demonstrates the key role of hydrophobic modification in designing effective oral nanocarriers, providing a promising platform for the treatment of intestinal diseases.

Transdermal insulin delivery in a painless, convenient, and on-demand way remains a long-standing challenge. A variety of smart microneedles (MNs) fabricated by glucose-responsive phenylboronic acid hydrogels have been previously developed to provide painless and autonomous insulin release in response to a glucose level change. However, like the majority of MNs, their transdermal delivery efficiency was still relatively low compared to that with subcutaneous injection. Herein, we report an iontophoresis (ITP)-integrated smart MNs delivery platform with enhanced transdermal delivery efficiency and delivery depth. Carbon nanotubes (CNTs) were induced in the boronate-containing hydrogel to develop a semi-interpenetrating network hydrogel with enhanced stiffness and conductivity. Remarkably, ITP not only facilitated efficient and deeper transdermal delivery of insulin via electroosmosis and electrophoresis but also well-maintained glucose responsiveness. This ITP-combined smart MNs delivery platform, which could provide on-demand insulin delivery in a painless, convenient, and safe way, is promising to achieve persistent glycemic control. Furthermore, transdermal delivery of payloads with a wide size range was achieved by this delivery platform and thus shed light on the development of an efficient transdermal delivery platform with deep skin penetration in a minimally invasive way.

Phenylboronic acid (PBA) is a widely exploited glucose-sensitive element for constructing glucose-responsive hydrogels to enable smart insulin delivery. However, its relatively high intrinsic pK_a affects its binding with glucose under physiological conditions and thus limits its application. Herein, we developed a series of boronate-containing PLP–PBA polymers by conjugating glucose-sensitive 3-aminophenylboronic acid (3-PBA) onto the backbone of a metabolite-derived, pH-responsive poly-L-lysine isophthalamide (PLP) polymer with a pK_a value of 4.4 at various substitution degrees. Dual-responsive LME–(PLP–PBA) hydrogels were further synthesized by crosslinking the PLP–PBA polymers with L-lysine methyl ester (LME). The rheological properties and swelling ratio of the hydrogel could be manipulated by the PBA grafting degree and crosslinking ratio. With the increase of pH and glucose concentration, the pore size of the hydrogel enhanced, thus promoting the release of loaded insulin. Under physiological conditions, the hydrogel with optimal formulation could establish acute pH-responsive and glucose-responsive insulin release. The development of this dual-responsive hydrogel suggests a strategy to overcome the high pK_a problem associated with PBA and provide a promising delivery system for smart insulin delivery.