Proteolysis targeting chimeras (PROTACs), heterobifunctional molecules that hijack the ubiquitin–proteasome system (UPS) to degrade specific proteins, hold great promise in treating diseases driven by traditionally “undruggable” targets. However, their large molecular weight, high hydrophobicity, and other physicochemical hurdles contribute to their limited bioavailability, suboptimal pharmacokinetics, and attenuated therapeutic efficacy. Consequently, diverse formulation innovations have been investigated to optimize PROTAC delivery. This review examines current challenges and advances in specialized drug delivery approaches designed to bolster PROTAC pharmacological performance. We first outline the fundamental limitations of PROTACs—their low aqueous solubility, poor cell permeability, rapid clearance, and concentration-dependent “hook effect”. We then discuss how various enabling formulations address these issues, including polymeric micelles, emulsions, amorphous solid dispersions, lipid-based nanoparticles, liposomes, and exosomes. Collectively, these delivery technologies substantially improve the therapeutic outcomes of PROTACs in preclinical cancer models. Future applications may extend beyond oncology to address other complex diseases using newly emerging heterobifunctional molecules. By integrating advanced formulation science with innovative degrader design, the field stands poised to unlock the clinical potential of PROTACs for protein degradation therapies.

Background/Objectives: Inhaler devices have been developed for the effective delivery of inhaled medications used in the treatment of pulmonary diseases. However, differing operating procedures across the devices can lead to user errors and reduce treatment efficacy, especially when patients use multiple devices simultaneously. To address this, we developed a novel dry powder inhaler (DPI), combining fluticasone propionate (FP), salmeterol xinafoate (SX), and tiotropium bromide (TB) into a single device designed for bioequivalent delivery compared to existing commercial products in an animal model. Methods: The micronized FP/SX/TB-loaded capsule was prepared by sieving, blending, and filling capsules. Capsule suitability of the drugs was investigated from the comparison of the stability of drugs within various capsule formulations to that of commercial products. The particle size of the drugs was adjusted using spiral air jet milling, and the ratio of lactose hydrate carriers was optimized by comparing the aerodynamic particle size distribution (APSD) with that of commercial products. To investigate the bioequivalence of micronized FP/SX/TB-loaded DPI to commercial products, the dissolution profile of FP/SX/TB particles and pharmacokinetics in rats were evaluated and compared to commercial products. Results: Capsules with hydroxypropyl methylcellulose (HPMC) without a gelling agent showed superior stability of the drugs compared to commercial products. The deposition pattern was influenced by the particle size of the drugs, and fine particle mass exhibited a significant correlation with the amount of fine carrier. Micronized FP/SX/TB-loaded DPI gave a similar APSD and dissolution profile compared to the commercial products and showed dose uniformity by the DPI device. Furthermore, micronized FP/SX/TB-loaded DPI exhibited bioequivalence to commercial products, as evidenced by no significant differences in pharmacokinetic parameters following intratracheal administration in rats. Conclusions: A novel triple-combination DPI containing FP/SX/TB was successfully developed, demonstrating comparable pharmacological performance to commercial products. Optimized FP/SX/TB-loaded DPI with HPMC capsule achieved bioequivalence in rat studies, suggesting its potential for improved patient compliance and therapeutic outcomes. This novel single-device DPI offers a promising alternative for triple therapy in pulmonary diseases.

Small-molecule immunomodulators have become important components of modern immunotherapy by targeting immune checkpoints, cytokine signaling pathways, metabolic enzymes, and intracellular kinases. Despite pharmacological rationale, many of these agents underperform clinically due to unfavorable physicochemical properties, rapid systemic clearance, limited target accumulation, and dose-limiting toxicities, reflecting inadequate exposure control rather than a lack of target validity. Polymeric micelles, formed through the self-assembly of amphiphilic block copolymers, offer a versatile delivery platform to address these challenges by enhancing solubility, modulating pharmacokinetics, enabling stimuli-responsive release, and facilitating targeted or synchronized co-delivery. In this review, we classify representative small-molecule immunomodulators according to their immunological targets and examine the delivery constraints that shape their therapeutic performance. We then discuss design principles of polymeric micelle systems, including solubilization-driven formulations, microenvironment-responsive architectures, spatial targeting strategies, and co-delivery approaches that align cytotoxic and immunomodulatory mechanisms. Attention is given to the distinction between direct immunomodulators and cytotoxic agents that induce immunogenic cell death, highlighting how micelle-based delivery can enhance efficacy through improved exposure control. By integrating immunopharmacology with formulation science, this review outlines how polymeric micelles may advance the efficacy and safety of small-molecule immunomodulators and identifies key considerations for future translational development.

Background: Ritonavir (RTV), an HIV-1 (human immunodeficiency virus-1) protease inhibitor, has low aqueous solubility and poor oral bioavailability, requiring large amounts of excipients that result in bulky dosage forms and poor patient compliance. We aimed to develop an RTV-loaded polymeric micelle formulation with high drug loading capacity that improves aqueous solubility, reduces the excipient burden and associated excipient-related adverse effects, and remains stable after lyophilization without a cryoprotectant. Methods: RTV-loaded micelles were prepared from the amphiphilic block copolymer poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) by thin-film hydration. Particle size and the polydispersity index (PDI) were measured by dynamic light scattering and encapsulation efficiency and drug content by HPLC, before and after lyophilization. The drug-to-excipient ratio was compared with the commercial product (Norvir^®), and pharmacokinetics were evaluated in male Sprague-Dawley rats after single oral administration. Results: Micelles showed a mean particle size of 25.9 ± 0.09 nm, a PDI of 0.224 ± 0.008, and an encapsulation efficiency of 98.9 ± 1.54%, with particle size and drug content retained after lyophilization and reconstitution without any cryoprotectant. Drug content reached 27.3% (w/w) versus 12.5% for the commercial product, a 2.6-fold reduction in excipients per unit dose. In rats, the micelle formulation showed pharmacokinetic parameters comparable to those of the Norvir^® suspension (C_max, 2243.9 ± 1226.4 vs. 2106.1 ± 835.9 ng/mL; AUC_last, 6695.3 ± 2162.6 vs. 8178.2 ± 2892.1 h·ng/mL; T_max, 0.9 ± 0.6 vs. 1.5 ± 0.5 h), with no significant differences. Conclusions: The PEG-b-PCL micelle achieved high RTV loading, substantially reduced excipients, and provided oral exposure comparable to the commercial product, supporting its potential as an alternative oral delivery system.