The pH-responsive DDS should be responsive and stable to slightly lower and physiological pH values (5.0–6.5, 7.4) for various biological applications. This design assists the therapeutics release inside the cell and surrounding tissues for the drug delivery purpose. This is because the endolysosomal sections are made upon internalization of several drug carriers. Additionally, the slight difference between the pH of tumor tissues versus normal tissue makes pH-responsiveness an ideal way to target the tumors with chemotherapeutics [
29]. For other biological applications, such as bioseparations, biofiltration, and anti-biofouling, the ranges of pH for response versus stability are case-specific, with a key parameter being the use of protein-friendly conditions that maintain bioactivity [
30]. Generally, two different strategies are being used to design the alternating copolymer-based pH-responsive self-assemblies. The first approach includes the incorporation of the acid-functionalized groups to the polymeric backbone. It may also be used to conjugate active drugs to the side chain of the polymer. These active drug groups may initiate the pH-response, which can accompany the conformational changes in all parts of the polymeric backbone. This change in conformation alters the nanostructures, which may result as self-assembly of the polymer. Following this pH-response phenomenon, several polymers, e.g., poly(lactic acid) (PLA), polycarbonates, poly(e-caprolactone) (PCL), acrylic acid, methacrylic acid (MAA), acrylonitrile (AN), polyketals, and polyanhydrides have been used to engineer pH-responsive DDS [
31,
32]. Consequently, the amphiphilic balance of the copolymer disrupts because of cleavage of the pH-triggered bond. This anomaly results in the breakage of the self-assembly or degrading of the nanocarrier and release of encapsulated therapeutics occur. The most striking nanocarriers for drug delivery purposes are degradable polymeric materials because these materials evade renal clearance [
33]. On the other hands, the drugs that are covalently attached to the carriers, have numerous advantages including enhanced drug stability, improved circulation time, improved biodistribution, and condensed drug toxicity. For example, Lee and coworkers have used a double-hydrophilic hyperbranched copolymer poly(ethylene glycol-hb-glycerol) (PEG-hb-PG), which can self-assemble into micelles. In these constructs, the doxorubicin (an anticancer drug) was incorporated into the PG unit of the hyperbranched polymer through acid-labile hydrazone linkages. This attachment reduces the hydrophobic character of the PG unit and the resulting amphiphilic copolymer formed micelles in aqueous solutions. Upon breaking the formed hydrazone bond at a pH = 5.0 (in solution), or in the endolysosomal parts of the HeLa cells, the doxorubicin was released, and the micelles disassembled into relatively smaller PEG-hb-PG monomers. Therefore, the arrangement of hyperbranched structure with-pH-cleavable entities results in the formation of biocompatible polymer with improved drug loading capacity and enhanced efficient release [
34]. Other important acid-cleavable structures that can be employed in copolymer assemblies include catechol, carbamate, and Schiff base [
35,
36]. The pH-responsive assemblies involve complete, or some part of the polymer, in triggering the stimuli-responsive alteration of the hydrophilic character, which results in the disruption of the self-assembling behavior of the nanostructure. pH-dependent swelling and drug release mechanism are shown in
Figure 4 [
36]. The hydrophilic changes that depend upon the pH have been widely used to activate the disassembling of the nanostructures into the monomers. For example, Manganiello and coworkers [
37] have reported the disassembly of the micelles at endosomal pH, which results in the enhanced release of the cytoplasmic delivery of the nucleic acid. In another approach, Doncom’s group [
38] benefiting from the pH-dependent protonation of amine groups presented a DDS that enhanced the hydrophilic character of an amphiphilic copolymer. This enhanced hydrophilic character leads to a pH-dependent transformation such as vesicle to micelle. Furthermore, the copolymer nanostructures can easily release a hydrophilic dye through the structural reorganization. These constructs can be applied as a pH-sensitive drug release system within tumor tissues or acidic intracellular portions. Sant et al. [
39] utilize the (PEG-b-P(AlA-co-MAA) block copolymer for the oral application of a pH-sensitive micelle. The formed aggregates release the drug at a physiological value of pH. In this approach, the deprotonation of the carboxyl group results in the transformation of the hydrophobic core into hydrophilic, which disrupts the self-assembly and releases the guest molecule.
Alternatively, the acid degradable units can also be used for the loading of the drug to the hydrophobic part of the amphiphilic polymer. Bae et al. used a block copolymer (PEG-b-PAsp) for the purpose. The doxorubicin drug was attached to the formed aggregates via a pH-responsive hydrazone bond [
40,
41]. Additionally, the micelle surface was functionalized with a folate ligand to increase the tumor-specific uptake. Aryal et al. [
42] used a similar linking behavior to the PEG-b-PLLA micelle for the delivery of cisplatin. Both systems operate well at pH 6 or lower for the enhanced release of drugs. Likewise, Bae et al. prepared charge-conversion micelles for the delivery of proteins. The micelles were formed as a result of attachment of methyl maleate to the aspartate block of a PEG-pAsp, which carry a negative charge under physiological conditions. The methyl maleate group breaks as these micelles enter the cell. This cleavage results in free positive charge (amine) and the loaded protein are released at endosomal pH (
Figure 5) [
42,
43,
44,
45].