**1. Introduction**

Proteins and peptides play vital roles in many biological processes, including catalysis, transportation, regulation of gene expression, immunity-related functions, etc. They are also involved in many pathological conditions such as diabetes, hypertension, cancer, etc. [1]. Because of their wide range of functions and their involvement in diseases, proteins and peptides are attractive therapeutic agents for combatting many diseases. Currently, there are more than 100 approved peptidebased therapeutics on the market [2]. The market for peptide and protein drugs is growing much faster than for small molecule drugs. One reason for this is that peptides and proteins can be highly selective as they have multiple points of interaction with the target. This increased selectivity will also lead to decreased side effects and toxicity.

However, the physicochemical properties of proteins and peptides make their use as drugs difficult. Firstly, proteins and peptides are not suitable for administration via the oral route because of their instability in the gastrointestinal tract (GIT). Secondly, the size and hydrophilicity of proteins and peptides lead to their poor bioavailability [3, 4]. Other routes of delivery also have some drawbacks. For example, administration via intravenous injection may not be suitable for achieving optimal therapeutic effects since many proteins and peptides have low circulation half-life [5]. This may also lead to pain or discomfort [6], severe reaction at the injection site [7, 8], scarring [9], local allergic reactions [10], cutaneous infections [11], etc. Transdermal delivery leads to absorption limitations due to the skin barrier, which prevents the passage of drug molecules with molecular weight greater than 500 Da, especially hydrophilic molecules [12, 13].

Extensive research has been performed over the past few decades to develop protein and peptide delivery systems that circumvent the drawbacks mentioned above. Different strategies that have been employed for this purpose include nanoparticle carriers, absorption enhancers, enzyme inhibitors, mucoadhesive polymers, and chemical modification of protein or peptide structures [14, 15]. Most of these approaches aim to deliver proteins and peptides via the oral route since it is the most convenient route of drug administration. However, other routes of administration such as transdermal [16], nasal [17], buccal [18], pulmonary [19] also have some attractive features such as avoidance of harsh environment of the GIT and non-invasiveness of the nature of administration. Thus, these routes can also be excellent alternatives for protein and peptide delivery [20]. This chapter will discuss the most effective approaches to developing protein and peptide drug delivery systems.

Proteins and peptides consist of amino acids connected via peptide bonds (**Figure 1**). Protein and peptide structures can be primary structure, secondary structure, tertiary structure, and quaternary structure. The primary structure provides information about the number and types of amino acids in a protein or peptide. Secondary structure gives us information about the presence of α-helix, β-sheets, loops, and turns in the protein or peptide. For example, hemoglobin is a predominantly helical protein (**Figure 2**). The tertiary structure indicates the overall three-dimensional structure of the protein. For example, the tertiary structure of hemoglobin consists of a globin fold (**Figure 2**). The quaternary structure indicates the oligomeric state of the protein. For example, hemoglobin has a tetrameric (or dimer of dimer) quaternary structure (**Figure 2**).

Various routes for delivery of protein and peptide drug has been mentioned above. Their advantages and disadvantages have been discussed briefly. The strategies adopted for enhancing the delivery of protein and peptides via various routes is discussed below.

**Figure 1.** *General structure of a peptide fragment.*

**Figure 2.** *Structure of hemoglobin.*
