Intelligent transdermal nanoparticles as synergizing advanced delivery systems for precision therapeutics

Abstract

Transdermal drug delivery systems (TDDS) represent a non-invasive approach to achieve controlled drug release through the skin barrier, offering stable plasma concentrations while avoiding gastrointestinal and hepatic metabolism. However, the skin barrier poses physical challenges, making it difficult for most drugs to penetrate deep tissues using TDDS. This review systematically summarizes the research progress in nanocarrier design, physical technology application, and artificial intelligence (AI)-driven TDDS optimization design aimed at overcoming the key problem of skin barrier penetration. An in-depth analysis of nanocarriers, such as soft vesicles, nanoemulsions, rigid nanoparticles, and physically assisted enhancement technologies, and AI-driven research on skin penetration enhancement in TDDS was summarized. An integrated technical framework demonstrates how microneedle arrays, iontophoresis, electroporation, and photoporation synergize with nanoparticles to achieve spatiotemporally controlled transdermal drug delivery. Additionally, the review emphasizes the clinical application potential of these integrated technologies and offers a comprehensive, multidimensional perspective to advance innovation in TDDS.

Keywords: Artificial intelligence; Clinical applications; Integrated strategies; Nanoplatforms; Physical enhancement technologies; Transdermal drug delivery.

Graphical abstract

Fig. 1

Schematic diagram of skin biological pathway of different nanomedicines through the skin (A), and various disease skin conditions (B). By Figdraw (www.figdraw.com).

Fig. 2

Preparation of HA-containing liposome (HL) and assessment of the effects of TDDS on acute skin injury. (A) Scheme of the HL preparation process. (B) Penetration of low molecular weight (MW) HA (LHA), high MW HA (HHA), LHA-liposome percutaneous system (LHL), and HHA-liposome percutaneous system (HHL) in acutely injured skin. (C) Effects of TDDS on inhibiting inflammatory effects and promoting tissue repair in Mice. Scale bars = 100 μm, 100 μm, and 50 μm (from left to right) [75]. Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd.

Fig. 3

The applications of AI in the TDDS field. (A) The training program for machine learning [205]. Copyright © 2023 Krishnagiri Krishnababu et al. The AI is used (B) to screen and predict the skin permeability digitally [209], (C) to design and optimize the TDDS [214] Copyright © 1999 Elsevier Science B.V., and (D) to identify potential chemical penetration enhancers (CPEs) [3,215]. By Figdraw (www.figdraw.com).

Fig. 4

A closed-loop framework integrates data, models, formulation, manufacturing, delivery, and optimization for intelligent TDDS.

Fig. 5

A framework for designing TDDS illustrating the typical compatibility between various classes of nanocarriers and their physical assistive technologies. The color scheme represents the compatibility strength of the reported combinations.

Fig. 6

Mechanisms of physical assistance to enhance transdermal absorption. (1) Creating microchannels to bypass the SC. (2) Changing drug distribution into the skin layer. (3) Disruption of the lipid bilayer of the SC. (4) Expanding intercellular channels of the SC.

Fig. 7

The application of physical assistive technology in TDDS. (A) Schematic illustrations of TDDS with iontophoresis for cancer treatment [253]. Copyright © 2023 Elsevier B.V. (B) carbon dioxide fractional laser-aided percutaneous delivery of SNF in a rabbit ear hypertrophic scars model. (a) Scheme of synergetic application of carbon dioxide fraction laser irradiation with R6G/R110-laden SNFs. (b) Representative images of normal skin (NS), hypertrophic scar (HS) tissue, and laser-treated HS specimens in a rabbit ear hypertrophic scar model. (Scale bar = 2.5 mm) [254]. Copyright © 2022, © The Yang (s) 2022. Published by Oxford University Press. (C) Schematic illustrations of the suggested in vivo electroporation methodology [255]. Copyright © The Huang (s) 2018. Published by Ivyspring International Publisher.

Fig. 8

The composition, mechanism, and characterization of H₂O₂-sensitive vesicles for glucose-sensitive insulin delivery. (A) The H₂O₂-sensitive polymeric vesicles (PVs) in their integration with a patch of percutaneous microneedle array and the triggering release mechanism. B (a) Fluorescent image of microneedles-laden PVs containing FITC-marked insulin. Scale bar = 200 μm. (b) The image of a microneedle patch by scanning electron microscopy. Scale bar = 200 μm. (C) The release dynamics of insulin in the media of different glucose concentrations. (D) Pulsatile release phenomena of insulin out of PVs when the glucose levels changed at a concentration of either 100 or 400 mg/dL. (E) Blood glucose levels of normal mice administered with a microneedle patch within 7 h after use [287]. Copyright © 2017, American Chemical Society.

Fig. 9

Scheme of a self-powered iontophoretic transdermal drug delivery system (TDDS) with unit harvesting biomechanical energy. (A) The logical structure of the self-powered iontophoretic unit and the scheme of delivering drugs to the skin. (B) Scheme of electrophoresis flow driven by wearable triboelectric nanogenerators (TENG). (C) Scheme of the structure of the hydrogel-contained soft patch for TDDS [299]. Copyright © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Fig. 10

Evaluation of the penetration of CAR@Lip gels, CAR@Lip, and free CAR in hair follicles and skin in vivo and in vitro. (a) Accumulated transdermal penetration, (b) transdermal flux, (c) and retention in the hair follicle (HF), stratum corneum (SC), and skin rest of CRA in (A) mouse skin and (B) pig ear skin. (C) The image of vertical tissue sections of P4@Liposome-treated skin specimens (capturing intact hair follicles). Blue fluorescent signals are DAPI-stained dermal nuclei, and red fluorescence signals represent the permeation and distribution of P4@Liposome and P4@Liposomal Gel in the skin. (Scale bar is 200 μm) [319]. Copyright © 2024, Controlled Release Society.

Fig. 11

Design and evaluation of the effect of calcium alginate hydrogel (NP/HAO) responsive to pH-containing fish sperm protein nanoparticles (NP) and hyaluronic acid oligosaccharide (HAO) in promoting diabetic wound healing. (A) Central hypothesis diagram of preparing process and efficacy of TDDS. (B) Evaluation of the healing of diabetic wounds promoted by PBS and CaAlg hydrogels [324]. Copyright © 2018, Controlled Release Society. Evaluating the effectiveness of nanolipid (NPImq) loaded with miglustat in treating skin cancer. (C) Preparation of BQ-788/NH ZnO loaded with EA (BQ-788/EA@ZnO quantum dots and skin penetration and performance of targeted melanocytes. The inhibiting effects of BQ-788/EA@ZnO quantum dots on TYR (D) and melanin internalization (E) within melanocytes [369]. Copyright © 2019 Elsevier B.V. All rights reserved.

Fig. 12

Schematic design of Sup-TDDS and evaluation of transdermal delivery capability. (A) The construction of self-assembled Sup-TDDS, synergistic chemotherapy, and PDT for non-invasive and synergistic melanoma treatment. (B) Ex vivo images of rat skin after Sup-TDDS treatment and then stained with anti-keratin 14. White arrows: the accumulation of Sup-TDDS within hair follicles. The scale bar is 200 μm [377]. Copyright © 2024 Wiley‐VCH GmbH. (C) Scheme of topical anesthesia treated with LidH-loaded elastic nanoliposomes (ENLs) after conditioning the skin using a solid microneedle (MN) array [379]. Copyright © 2021 Liu et al.