Compositions and Methods for Treating Neurological-associated Disorders

1 . A composition comprising: (i) a CNS targeting agent; and (ii) a neurotrophic factor, wherein the CNS targeting agent and the neurotrophic factor are linked to a clathrin nanoparticle.

2 . The composition of claim 1 , wherein the clathrin nanoparticle comprises a clathrin cage.

3 . The composition of claim 1 , wherein the clathrin nanoparticle consists of a clathrin triskelion.

4 . The composition of claim 1 , wherein the clathrin nanoparticle comprises a complex consisting of 1 to 3 clathrin heavy chains.

5 . The composition of claim 1 , wherein the neurotrophic factor is a neurotrophic factor that binds to tropomyosin-related kinase receptor, optionally TrkA, TrkB, and/or TrkC, NT-3 receptor, NT-4 receptor, NT-5 receptor, neurturin receptor, persephin receptor, artemin receptor, ciliary neurotrophic factor receptor, p75 neurotrophin receptor, or leukemia inhibitory factor receptor.

6 . The composition of claim 1 , wherein the neurotrophic factor is linked to the clathrin nanoparticles by conjugation.

7 . The composition of claim 6 , wherein the neurotrophic factor is conjugated to the clathrin nanoparticles via PEG.

8 . The composition of claim 4 , wherein a clathrin heavy chain of the clathrin triskelion is linked to 1 to 5 molecules of the neurotrophic factor.

9 . The composition of claim 4 , wherein the clathrin nanoparticle comprises a complex consisting of 3 clathrin heavy chains.

10 . The composition of claim 4 , wherein each of the clathrin heavy chains is linked to 1 to 5 molecules of the neurotrophic factor.

11 . The composition of claim 9 , wherein each of the clathrin heavy chains is linked to 1 molecule of the neurotrophic factor.

12 . The composition of claim 1 , wherein the neurotrophic factor is NT-3, NT-4, NT-5, NT-6, neurturin, persephin, artemin, ciliary neurotrophic factor, nerve growth factor (NGF), or leukemia inhibitory factor.

13 . The composition of claim 1 , wherein the CNS targeting agent is an antibody.

14 . The composition of claim 13 , wherein the antibody comprises an anti-CD11b antibody, an anti-TrkB receptor antibody, an anti-DAT antibody, an anti-GABA antibody, an anti-SYP antibody, an anti-serotonin transporter antibody, an anti-dopamine-1 antibody, an anti-dopamine-2 antibody, an anti-dopamine-3 antibody, an anti-TREM2-antibody, an IL-6R-antibody, or an anti-TNF-α-antibody.

15 . The composition of claim 14 , wherein the antibody is a monoclonal antibody.

16 . The composition of claim 1 , wherein the CNS targeting agent is a ligand.

17 . The composition of claim 16 , wherein the ligand comprises a DAT ligand, a TSPO ligand, a GABA ligand, a serotonin transporter ligand, a D1 ligand, a D2 ligand, or a D3 ligand.

18 . The composition of claim 1 , further comprising an imaging contrast agent.

19 . The composition of claim 18 , wherein the imaging contrast agent comprises a gadolinium (Gd) based contrast agent, manganese-based, superparamagnetic iron oxide (SPIO), monocrystalline iron oxide nanoparticle (MION), cross-linked iron oxide (CLIO), or magneto-dendrimer contrast agent.

20 . The composition of claim 1 , further comprising one or more additional therapeutic agent.

21 . The composition of claim 21 , wherein the additional therapeutic agent comprises aripiprazole, baclofen, bupropion, d-AMP and MPH-SR, dextroamphetamine, gabapentin, ibudilast, methylphenidate, mirtazapine, modafinil, NAC, naltrexone, rivastigmine, or topiramate.

22 . The composition of claim 1 , further comprising, the neurotrophic agent, targeting agent, imaging contrast agent and/or additional therapeutic agent linked together with the clathrin nanoparticle.

23 . A method for treating a human subject having or at risk for developing a neurodegenerative disorder, optionally Alzheimer's disease, HIV- Associated Neurocognitive Disorder (HAND), Parkinson's disease, or Huntington's diseases; a neuroinflammatory disease, optionally amyotrophic lateral sclerosis or multiple sclerosis; stroke; a neurological disorder associated with COVID-19, optionally a cognitive deficit; traumatic brain injury; or a psychiatric disorder, optionally depression, comprising administering to the human subject a composition comprising: (i) a CNS targeting agent; and (ii) a neurotrophic factor, wherein the CNS targeting agent and the neurotrophic factor are linked to a clathrin nanoparticle.

24 . The method of claim 23 , wherein the clathrin nanoparticle comprises a clathrin cage.

25 . The method of claim 23 , wherein the clathrin nanoparticle consists of a clathrin triskelion.

26 . The method of claim 24 , wherein the clathrin nanoparticle comprises a complex consisting of 1 to 3 clathrin heavy chains.

27 . The method of claim 23 , wherein the neurotrophic factor is a neurotrophic factor that binds to tropomyosin-related kinase receptor, optionally TrkA, TrkB, and/or TrkC; NT-3 receptor; NT-4 receptor; NT-5 receptor; neurturin receptor; persephin receptor; artemin receptor; ciliary neurotrophic factor receptor; p75 neurotrophin receptor; or leukemia inhibitory factor receptor.

28 . The method of claim 23 , wherein the neurotrophic factor is linked to the clathrin nanoparticles by conjugation.

29 . The method of claim 28 , wherein the neurotrophic factor is conjugated to the clathrin nanoparticles via PEG.

30 . The method of claim 26 , wherein a clathrin heavy chain of the clathrin triskelion is linked to 1 to 5 molecules of the neurotrophic factor.

31 . The method of claim 26 , wherein the clathrin nanoparticle comprises a complex consisting of 3 clathrin heavy chains.

32 . The method of claim 26 , wherein each of the clathrin heavy chains is linked to 1 to 5 molecules of the neurotrophic factor.

33 . The method of claim 31 , wherein each of the clathrin heavy chains is linked to 1 molecule of the neurotrophic factor.

34 . The method of claim 23 , wherein the neurotrophic factor is NT-3, NT-4, NT-5, NT-6, neurturin, persephin, artemin, ciliary neurotrophic factor, nerve growth factor (NGF), or leukemia inhibitory factor.

35 . The method of claim 23 , wherein the CNS targeting agent is an antibody.

36 . The method of claim 35 , wherein the antibody comprises wherein the antibody comprises an anti-CD11b antibody, an anti-TrkB receptor antibody, an anti-DAT antibody, an anti-GABA antibody, an anti-SYP antibody, an anti-serotonin transporter antibody, an anti-dopamine-1 antibody, an anti-dopamine-2 antibody, an anti-dopamine-3 antibody, an anti-TREM2-antibody, an IL-6R-antibody, or an anti-TNF-α-antibody.

37 . The method of claim 36 , wherein the antibody is a monoclonal antibody.

38 . The method of claim 23 , wherein the CNS targeting agent is a ligand.

39 . The method of claim 38 , wherein the ligand comprises a DAT ligand, a TSPO ligand, a GABA ligand, a serotonin transporter ligand, a D1 ligand, a D2 ligand, or a D3 ligand.

40 . The method of claim 23 , wherein the clathrin nanoparticle further comprises an imaging contrast agent.

41 . The method of claim 40 , wherein the imaging contrast agent comprises a gadolinium (Gd) based contrast agent, manganese-based, superparamagnetic iron oxide (SPIO), monocrystalline iron oxide nanoparticle (MION), cross-linked iron oxide (CLIO), or magneto-dendrimer contrast agent.

42 . The method of claim 23 , wherein the HIV-Associated Neurocognitive Disorder is asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), or HIV associated dementia (HAD).

43 . The method of claim 23 , further comprising one or more additional therapeutic agent.

44 . The method of claim 43 , wherein the additional therapeutic agent comprises aripiprazole, baclofen, bupropion, d-AMP, MPH-SR, dextroamphetamine, gabapentin, ibudilast, methylphenidate, mirtazapine, modafinil, NAC, naltrexone, rivastigmine, or topiramate.

45 . The method of claim 23 , further comprising, the neurotrophic agent, targeting agent, imaging contrast agent and/or additional therapeutic agent linked together with the clathrin nanoparticle.

46 . The method of claim 23 , further comprising imaging a region of the brain using the contrast agent during a course of treating the neurodegenerative disorder.

47 . The method of claim 23 , wherein the composition is delivered intranasally or intravenously.