**Background:** Posterior segment ocular diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and uveitis, account for 55% of all ocular diseases and are a leading cause of vision impairment. Drug delivery to the retina is hindered by static barriers (cornea, sclera, blood–aqueous and blood–retinal barriers) and dynamic barriers (tear turnover, lymphatic clearance). Topical eyedrops provide only 5% bioavailability, and intravitreal injections are invasive, painful, and carry infection risks. This mini-review highlights innovative strategies to overcome these barriers, focusing on nanotechnologies, penetration enhancers, and sustained-release systems.
**Methods:** A literature search was conducted in MEDLINE (PubMed) from 1 January 2002 to 28 February 2023 using keywords "drug delivery system, ocular posterior segment, AND vitreoretinal, AND nanotechnologies AND matrices." Only English-language studies with abstracts were included. Two reviewers independently assessed 233 references. The search may have unintentionally excluded some opinion leaders.
**Key Results:** The review categorizes DDSs into nanomedicine, topical absorption enhancers, and sustained-release systems.
- **Nanomedicine:** Liposomes (e.g., Visudyne for choroidal neovascularization) are FDA-approved but face instability and aggregation issues. Nanomicelles (5–30 nm) can deliver hydrophobic drugs like rapamycin to the choroid and retina via topical administration. Dendrimers (1–100 nm) loaded with dexamethasone reduced neuroinflammation and halted photoreceptor loss for 4 weeks in retinal degeneration mice. Organic nanopolymers like PLGA (FDA-approved) sustained 50% of dexamethasone levels for one month vs. 7 days with solution. Chitosan-based nanoparticles enhanced drug residence time; carboxymethyl chitosan-coated nanocomposites delivered higher dexamethasone concentrations to the retina-choroid via the conjunctival-scleral pathway. Metallic nanoparticles (e.g., 20 nm gold NPs) crossed the blood–retinal barrier, and nanoceria protected retinal cells from oxidation for over 1 year in murine models.
- **Topical Absorption Enhancers:** Cell-penetrating peptides (CPPs) like TAT conjugated to endostatin reduced choroidal neovascularization areas comparably to intravitreal anti-VEGF. Penetratin showed retinal uptake within 10 minutes, peaking at 30 minutes, with low cytotoxicity (IC50 2.5 mM). Cyclodextrins (e.g., γCD) improved dexamethasone retinal concentration; in a clinical trial, 1.5% dexamethasone/γCD eyedrops reduced central macular thickness from 512 ± 164 µm to 399 ± 154 µm (p = 0.0016) in diabetic macular edema patients. Iontophoresis (EyeGate II) delivered dexamethasone phosphate transsclerally, achieving vitreous concentrations above anti-inflammatory thresholds.
- **Sustained-Release Systems:** Ocular inserts (e.g., melt-cast films) generated higher drug levels in retina-choroid vs. controls. Non-biodegradable implants (e.g., Retisert, Iluvien) provide sustained fluocinolone acetonide release for uveitis and DME. Biodegradable implants (e.g., Ozurdex) release 0.7 mg dexamethasone for up to 6 months. Hydrogels (e.g., hyaluronic acid-based) sustained bevacizumab release for >400 days in vitro. Contact lenses (e.g., Dex-DS) achieved retinal drug concentrations 200 times greater than hourly dexamethasone drops. Microneedles (e.g., SCS Microinjector) enable suprachoroidal delivery of triamcinolone acetonide (Xipere) for uveitic macular edema.
**Clinical Implications:** These innovative DDSs aim to replace frequent intravitreal injections with less invasive, sustained-release alternatives, improving patient compliance and reducing side effects. However, most technologies remain preclinical; only a few (e.g., Visudyne, Ozurdex, Retisert, Iluvien, Xipere) are clinically approved. Challenges include nanoparticle stability, cytotoxicity (e.g., dendrimers, metallic NPs), limited drug loading, and need for surgical implantation. Future research must focus on translating preclinical success into clinical trials, optimizing safety, and addressing patient comfort.