Painless methods that provide alternatives to oral, nasal, ocular, rectal, or pulmonary routes for therapeutic drug delivery are referred to as minimally invasive drug administration. Polyvinylpyrrolidone polymer with varying molecular weights was used to create microneedles. The polymer contained three model molecules with increasing MW: fluorescein sodium and fluorescein isothiocyanate–dextrans. Biomacromolecule transdermal distribution without needles is still a difficulty. This study develops a transdermal delivery platform utilizing nontoxic fluorocarbon-modified chitosan (FCS) to facilitate the noninvasive, highly effective distribution of biomacromolecules, such as antigens and antibodies. The resulting nanocomplexes demonstrate efficient transdermal penetration through both transappendageal and intercellular pathways. Compared to intravenous injection, noninvasive transdermal administration of immune checkpoint inhibitor antibodies decreases systemic toxicity and strengthens immune responses against melanoma in female mice. In order to regulate glucose levels in the blood and time, there has been a great deal of research interest in creating new insulin administration technologies that can also improve patient compliance by using noninvasive delivery methods. This chapter’s focus is on different, less intrusive medication delivery methods, such as biological macromolecules. This chapter also discusses several smart stimuli-responsive techniques, kinds of minimally invasive medication delivery, case studies, and applications. Lastly, a thorough discussion of the benefits, drawbacks, and implications of each minimally invasive method for delivering biological macromolecules is presented.