EMERGING TRENDS IN STIMULI-SENSITIVE DRUG DELIVERY SYSTEM: A COMPREHENSIVE REVIEW OF CLINICAL APPLICATIONS AND RECENT ADVANCEMENTS Review Article THAMARAI SELVAN DHANDAPANI 1 , VIJAYARAGHAVAN KRISHNAN 1 , BALAGEE MUTHUKUMAR 2 , VIVEKANANDAN ELANGO 1 , SAKTHI SHANMUGA JEYANDAR LAKSHMANAN 1 , SAM HARRISON SAM JENKINSON 3 , DHANDAPANI NAGASAMY VENKATESH 1* 1 Department of Pharmaceutics, JSS College of Pharmacy, (JSS Academy of Higher Education and Research, Mysuru) Ooty - 643 001. Nilgiris. Tamil Nadu, India. 2 Department of Pharmaceutical Analysis, JSS College of Pharmacy, (JSS Academy of Higher Education and Research, Mysuru) Ooty - 643 001. Nilgiris. Tamil Nadu. India. 3 Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, (JSS Academy of Higher Education and Research, Mysuru) Ooty - 643 001. Nilgiris. Tamil Nadu. India. * Corresponding author: Dhandapani Nagasamy Venkatesh; * Email: nagasamyvenkatesh@jssuni.edu.in Received: 27 Jul 2023, Revised and Accepted: 26 Aug 2023 ABSTRACT The combination of fields such as applied physics, biology, computational modeling and analysis, pharmaceuticals, chemistry, optics, and material science study has been made easier for the rise of stimuli-sensitive drug delivery systems. This study aimed to overcome the shortcomings of conventional therapeutic approaches by concentrating on the most recent developments in stimuli-sensitive drug delivery systems, which are intended to accomplish the targeted release of drugs in specified areas. This review aims to provide an overview of stimuli-sensitive drug delivery systems and recent advancements between 2015 and 2023 by focusing on their ability to respond to exogenous and endogenous stimuli. In recent years, significant progress has been made in developing innovative stimuli-responsive drug delivery platforms that can trigger various external stimuli, such as light, temperature, magnetic fields, and ultrasound. These exogenous stimuli-responsive systems enable on-demand drug release at specific target sites, allowing for personalized and patient-centric treatment strategies. Notable breakthroughs include photoresponsive nanocarriers, thermosensitive hydrogels, and magnetic nanoparticles, all designed to respond to specific cues for controlled drug delivery. Keywords: Stimuli-sensitive drug delivery systems, Exogenous stimuli, Endogenous stimuli, Recent advancements © 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2023v15i6.48974. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION A stimuli-sensitive drug delivery system is a sophisticated platform designed to respond intelligently to specific triggers from external sources (exogenous stimuli) and internal cues within the body (endogenous stimuli). These triggers include light, temperature, magnetic fields, ultrasound, pH levels, enzymatic activity, and more. By exploiting the potential of these stimuli, stimuli-sensitive drug delivery systems can achieve accurate drug release at specific locations, maximizing therapeutic results and minimizing potential adverse reactions [1]. This article will explore the fascinating world of stimuli-sensitive drug delivery systems. We will focus on two crucial aspects: the diverse range of exogenous and endogenous stimuli that can trigger drug release and the recent ground-breaking advancements that have propelled this field to new heights. By obtaining a comprehensive understanding of the fundamental principles and the latest innovations, we can better appreciate the immense potential of intelligent drug administration systems in revolutionizing patient treatments and ushering in a new era of personalized medicine. So, let us embark on this journey through cutting-edge advancements in drug delivery, where science meets resourcefulness to redefine the panorama of healthcare. Stimuli-sensitive drug delivery systems A recent advanced method for drug targeting is the Stimuli-sensitive drug delivery system. In a stimuli-sensitive drug delivery system, the medication is directly delivered to the target site or released whenever necessary, thereby reducing the adverse effects of medication in other tissues [2]. Medication is selectively accumulated in the target site for a prolonged period in a highly controlled manner for enhancing the therapeutic activity in the stimuli-sensitive drug delivery system [3]. An ideal stimuli-sensitive drug delivery system should meet several critical criteria. Firstly, the material used to create the system’s matrix should be biocompatible or at least not adversely affect the body. Secondly, the medication should be able to be encapsulated within the system without losing its effectiveness. Thirdly, the release of the drug should be able to be triggered in a non-invasive way without requiring any external devices. Finally, the system should ensure that no medication is released until it is activated or turned on [4]. Classification is based on the mechanism by which drug release Endogenous stimulus The term "endogenous stimulus," also called intrinsic stimulus, pertains to a scenario wherein the triggering signal originates within the body. This signal is generated explicitly by factors such as the internal pH level, redox activity, and enzyme activity. These drug delivery systems initiate the administration of medications by controlling the conditions within the tissues, increasing the activity of particular enzymes, facilitating the interaction between antibodies and antigens, and identifying specific configurations of host-guest molecules [5]. pH-responsive drug delivery system pH-susceptible polymers are a kind of polymers that demonstrate a reply to fluctuations in the encompassing pH levels. These polymers can be sorted into two categories: (A) polymers with ionizable functional groups and (B) polymers containing acid-degradable bonds. The ionization of the connected acidic or fundamental groups is prompted by the change in environmental pH, which causes cross- linking and modifications to the polymer's swelling properties [6]. To demonstrate, when subjected to a low pH environment, polyacid polymers undergo a decrease in size, whereas, in a high pH environment, they encounter an extension due to the protonation of their acidic components [7]. Combining pH-sensitive drug-release systems with other stimuli, redox, or temperature triggers enhances the accuracy and efficacy of these systems in responding to multiple parameters. For example, PEG-grafted PMAAc demonstrates notable sensitivity to changes in pH levels. For instance, To achieve specific delivery of 5-Fluorouracil (5-FU) to the colon, researchers developed a method utilizing citrus pectin nanoparticles (E-CPNs) coated with Eudragit S100 [8]. Polymers that respond to changes in pH International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 15, Issue 6, 2023