Pooyan Makvandi 1, ⇑ ,† , Rezvan Jamaledin 2,3,† , Guojun Chen 4,5,† , Zahra Baghbantaraghdari 2,3,† , Ehsan Nazarzadeh Zare 6 , Concetta di Natale 2,3 , Valentina Onesto 2 , Raffaele Vecchione 2 , Jesse Lee 5 , Franklin R. Tay 7 , Paolo Netti 2,3 , Virgilio Mattoli 1 , Ana Jaklenec 8 , Zhen Gu 4,9,10, ⇑ , Robert Langer 8 1 Istituto Italiano di Tecnologia, Centre for Materials interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Pisa, Italy 2 Center for Advanced Biomaterials for Health Care (iit@CRIB), Istituto Italiano di Tecnologia, Naples, 80125, Italy 3 Department of Chemical, Materials & Industrial Production Engineering, University of Naples Federico II, Naples, 80125, Italy 4 Department of Bioengineering and California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA 5 Department of Biomedical Engineering, and the Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, H3G 0B1, Canada 6 School of Chemistry, Damghan University, Damghan, 36716-41167, Iran 7 College of Graduate Studies, Augusta University, Augusta, GA, 30912, USA 8 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA 9 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095, United States 10 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China Microneedle (MN) patches consisting of miniature needles have emerged as a promising tool to perforate the stratum corneum and translocate biomolecules into the dermis in a minimally invasive manner. Stimuli-responsive MN patches represent emerging drug delivery systems that release cargos on-demand as a response to internal or external triggers. In this review, a variety of stimuli-responsive MN patches for controlled drug release are introduced, covering the mechanisms of action toward different indications. Future opportunities and challenges with respect to clinical translation are also discussed. Introduction Conventional routes of drug administration, such as oral and parenteral routes, often have limitations due to the drug’s physicochemical properties. For instance, oral administrations are associated with the first-pass metabolism, which greatly reduces the bioavailability reduce bioavaibility of delivered ther- apeutics. Injection is invasive, which generally requires adminis- tration by trained personnel and is usually painful and potentially associated with needle phobia in patients, especially children [1,2]. Conversely, microneedles (MNs) are capable of penetrating the outermost layer of the skin (stratum corneum) to locally administer bioactive molecules into the epidermis and/ or superficial dermis. Microneedles offer an appealing adminis- tration approach to patients as this method of administration is painless and may be self-administered [3–8]. Recently, stimuli-responsive MNs, typically based on poly- meric matrices, have been introduced to facilitate and control the release of payloads [7,9]. Stimuli-responsive materials com- prise a wide range of compounds that are capable of responding to changes in their surrounding environment (Fig. 1) [10,11]. The responses of stimuli-responsive materials to the environ- ment may be in the form of formulation dissociation, matrix degradation, cleavage from matrix, and matrix swell [12,13]. These systems release payloads in response to physiological sig- nals as internal stimuli (e.g., pH, redox potential, glucose and enzymes) [14,15] and/or physical signals as external stimuli (e.g., temperature, electric field, light, and mechanical stress) Stimuli-responsive transdermal microneedle patches for drug delivery ⇑ Corresponding authors. E-mail addresses: Makvandi, P. (pooyan.makvandi@iit.it), (pooyanmakvandi@gmail.com), Gu, Z. (guzhen@zju.edu.cn). † Equal contributors. 1369-7021/Ó 2021 The Authors. Published by Elsevier Ltd. https://doi.org/10.1016/j.mattod.2021.03.012This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1 Materials Today d Volume xxx, Number xx d xxxx 2021 RESEARCH RESEARCH: Review Please cite this article in press as: P. Makvandi et al., Materials Today, (2021), https://doi.org/10.1016/j.mattod.2021.03.012